INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(21137073, 'Kikuta K, Tochigi N, Saito S, Shimoda T, Morioka H, Toyama Y, Hosono A, Suehara Y, Beppu Y, Kawai A, Hirohashi S, Kondo T', 'Peroxiredoxin 2 as a chemotherapy responsiveness biomarker candidate in osteosarcoma revealed by proteomics.', 'Proteomics Clin Appl', '2010', 'Peroxiredoxin 2 as a chemotherapy responsiveness biomarker candidate in osteosarcoma revealed by proteomics. We aimed to identify novel chemotherapy responsiveness biomarkers for osteosarcoma (OS) by investigating the global protein expression profile of 12 biopsy samples from OS patients.Six patients were classified as good responders and six as poor responders, according to the Huvos grading system. The protein expression profiles obtained by 2-D DIGE consisted of 2250 protein spots.Among them, we identified 55 protein spots whose intensity was significantly different (Bonferroni adjusted p-value<0.01) between the two patient groups. Mass spectrometric protein identification demonstrated that the 55 spots corresponded to 38 distinct gene products including peroxiredoxin 2 (PRDX 2). Use of a specific antibody against PRDX 2 confirmed the differential expression of PRDX 2 between good and poor responders, while PRDX 2 levels as measured by Western blotting correlated highly with their corresponding 2-D DIGE values. The predictive value of PRDX 2 expression was further confirmed by examining an additional four OS cases using Western blotting.These results establish PRDX 2 as a candidate for chemotherapy responsiveness marker in OS. Measuring PRDX 2 in biopsy samples before treatment may contribute to more effective management of OS.Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.', 'http://www.ncbi.nlm.nih.gov/pubmed/21137073', 'yes', 'yes', 'NA', 1),
(21145881, 'Huang CY, Lee CY, Chen MY, Tsai HC, Hsu HC, Tang CH', 'Nephroblastoma overexpressed gene (NOV) enhances cell motility and COX-2 upregulation of human osteosarcoma involves αvβ5 integrin, ILK and AP-1-dependent pathways.', 'Biochem Pharmacol', '2011', 'Nephroblastoma overexpressed gene (NOV) enhances cell motility and COX-2 upregulation of human osteosarcoma involves αvβ5 integrin, ILK and AP-1-dependent pathways. Osteosarcoma is characterized by a high malignant and metastatic potential. Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin synthase, has been implicated in tumor metastasis. Nephroblastoma overexpressed gene (NOV), also called CCN3, was regulated proliferation and differentiation of cancer cells. However, the effect of NOV on migration activity and COX-2 expression in human osteosarcoma cells is mostly unknown. Here we found that NOV increased the migration and expression of COX-2 in human osteosarcoma cells. αvβ5 monoclonal antibody (mAb), integrin-linked kinase (ILK) and Akt inhibitor reduced the NOV-enhanced the migration and COX-2 up-regulation of osteosarcoma cells. NOV stimulation increased the ILK kinase activity and phosphorylation of Akt. In addition, c-Jun siRNA also antagonized the NOV-mediated migration and COX-2 expression. Moreover, NOV enhanced the AP-1 binding activity and promoter activity. Taken together, these results suggest that the NOV acts through αvβ5 integrin to activate ILK and Akt, which in turn activates c-Jun and AP-1, resulting in the activations of COX-2 and contributing the migration of human osteosarcoma cells.Copyright © 2011 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21145881', 'no', 'no', 'NA', 7),
(21149578, 'Iizuka S, Kudo Y, Yoshida M, Tsunematsu T, Yoshiko Y, Uchida T, Ogawa I, Miyauchi M, Takata T', 'Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via cross talk between integrin beta1 and CD63.', 'Mol Cell Biol', '2011', 'Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via cross talk between integrin beta1 and CD63. Ameloblastin, the most abundant nonamelogenin enamel matrix protein, plays a role in ameloblast differentiation. Here, we found that ameloblastin was expressed in osteosarcoma cells; to explore the potential functions of ameloblastin in osteoblasts, we investigated whether this protein is involved in osteogenic differentiation and bone formation on the premise that CD63, a member of the transmembrane-4 glycoprotein superfamily, interacts with integrins in the presence of ameloblastin. Ameloblastin bound to CD63 and promoted CD63 binding to integrin β1. The interaction between CD63 and integrin β1 induced Src kinase inactivation via the binding of CD63 to Src. The reduction of Src activity and osteogenic differentiation mediated by ameloblastin were abrogated by treatment with anti-CD63 antibody and overexpression of constitutively active Src, respectively. Therefore, our results suggest that ameloblastin is expressed in osteoblasts and functions as a promoting factor for osteogenic differentiation via a novel pathway through the interaction between CD63 and integrin β1.', 'http://www.ncbi.nlm.nih.gov/pubmed/21149578', 'no', 'no', 'NA', 4),
(21152068, 'Rastegar F, Gao JL, Shenaq D, Luo Q, Shi Q, Kim SH, Jiang W, Wagner ER, Huang E, Gao Y, Shen J, Yang K, He BC, Chen L, Zuo GW, Luo J, Luo X, Bi Y, Liu X, Li M, Hu N, Wang L, Luther G, Luu HH, Haydon RC, He TC', 'Lysophosphatidic acid acyltransferase β (LPAATβ) promotes the tumor growth of human osteosarcoma.', 'PLoS One', '2010', 'Lysophosphatidic acid acyltransferase β (LPAATβ) promotes the tumor growth of human osteosarcoma. Osteosarcoma is the most common primary malignancy of bone with poorly characterized molecular pathways important in its pathogenesis. Increasing evidence indicates that elevated lipid biosynthesis is a characteristic feature of cancer. We sought to investigate the role of lysophosphatidic acid acyltransferase β (LPAATβ, aka, AGPAT2) in regulating the proliferation and growth of human osteosarcoma cells. LPAATβ can generate phosphatidic acid, which plays a key role in lipid biosynthesis as well as in cell proliferation and survival. Although elevated expression of LPAATβ has been reported in several types of human tumors, the role of LPAATβ in osteosarcoma progression has yet to be elucidated.Endogenous expression of LPAATβ in osteosarcoma cell lines is analyzed by using semi-quantitative PCR and immunohistochemical staining. Adenovirus-mediated overexpression of LPAATβ and silencing LPAATβ expression is employed to determine the effect of LPAATβ on osteosarcoma cell proliferation and migration in vitro and osteosarcoma tumor growth in vivo. We have found that expression of LPAATβ is readily detected in 8 of the 10 analyzed human osteosarcoma lines. Exogenous expression of LPAATβ promotes osteosarcoma cell proliferation and migration, while silencing LPAATβ expression inhibits these cellular characteristics. We further demonstrate that exogenous expression of LPAATβ effectively promotes tumor growth, while knockdown of LPAATβ expression inhibits tumor growth in an orthotopic xenograft model of human osteosarcoma.Our results strongly suggest that LPAATβ expression may be associated with the aggressive phenotypes of human osteosarcoma and that LPAATβ may play an important role in regulating osteosarcoma cell proliferation and tumor growth. Thus, targeting LPAATβ may be exploited as a novel therapeutic strategy for the clinical management of osteosarcoma. This is especially attractive given the availability of selective pharmacological inhibitors.', 'http://www.ncbi.nlm.nih.gov/pubmed/21152068', 'no', 'no', 'NA', 1),
(21159888, 'Ito M, Barys L, O''Reilly T, Young S, Gorbatcheva B, Monahan J, Zumstein-Mecker S, Choong PF, Dickinson I, Crowe P, Hemmings C, Desai J, Thomas DM, Lisztwan J', 'Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis.', 'Clin Cancer Res', '2011', 'Comprehensive mapping of p53 pathway alterations reveals an apparent role for both SNP309 and MDM2 amplification in sarcomagenesis. Reactivation of p53 tumor suppressor activity in diseases such as soft-tissue sarcoma is considered an attractive means of targeted therapy. By systematically assessing alterations affecting the p53 pathway, we aimed to (a) classify sarcoma subtypes, (b) define a potential role in malignancy, and (c) identify potential patient biomarkers in this heterogeneous disease.We have mapped mutational events in a panel of 192 benign or malignant bone and soft-tissue sarcomas. Analyses included TP53 and CDKN2A mutational and SNP status, MDM2 and MDM4 amplification and MDM2 SNP309 status.We found an inverse relationship between MDM2 amplification and TP53 mutations, with a predominantly wild-type CDKN2A background. A high rate of point mutations in TP53 was observed uniquely in leiomyosarcoma, osteosarcoma, and MFH. Both MDM2 and MDM4 were also amplified in a subtype-specific manner, which was frequently seen as a coamplification event. We have also analyzed the risk allele frequencies for MDM2 SNP309, and show that the G allele was strongly associated with both liposarcomas and MDM2 amplification.Our data emphasize the critical role of p53 inactivation in sarcomagenesis, whereby different pathway alterations may be related to the heterogeneity of the disease. Moreover, we observed a strong association of malignancy with TP53 mutation, or MDM2 amplification and the presence of a G allele in SNP309, especially in lipoma versus liposarcoma. We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.©2010 AACR.', 'http://www.ncbi.nlm.nih.gov/pubmed/21159888', 'yes', 'no', 'NA', 4),
(21163271, 'Li X, Zhao Y, Wu WK, Liu S, Cui M, Lou H', 'Solamargine induces apoptosis associated with p53 transcription-dependent and transcription-independent pathways in human osteosarcoma U2OS cells.', 'Life Sci', '2011', 'Solamargine induces apoptosis associated with p53 transcription-dependent and transcription-independent pathways in human osteosarcoma U2OS cells. Solamargine, a steroidal glycoalkaloid isolated from S. incanum, has been shown to induce apoptosis in several cancer cell lines. In this study, the involvement of p53 in the pro-apoptotic action of solamargine was investigated in human osteosarcoma U2OS cells.The cytotoxicity of solamargine was evaluated by MTT assay. Solamargine-induced apoptosis was evidenced by chromatin condensation, formation of apoptotic bodies and exposure of phosphatidylserine on the extracellular surface as revealed by DAPI nuclear staining, transmission electron microscopy and flow cytometry, respectively. mRNA expressions of p53 and Bax were investigated using real time-PCR. Western blot was used to examine the changes in the expression levels of p53, Bax, Bcl-2, caspase-3, caspase-9 and cytochrome c. Subcellular localization of p53 was verified by immunofluorescence staining and cell fractionation.Solamargine substantially reduced cell viability and induced apoptosis in osteosarcoma U2OS cells. In this connection, solamargine increased the mRNA and protein expressions of p53 and Bax (a pro-apoptotic protein downstream to p53). The expression of Bcl-2 (an anti-apoptotic protein) was also reduced. Furthermore, solamargine induced mitochondrial translocation of p53, loss of mitochondrial membrane potential, cytochrome c release and activation of caspase-9 and -3. p53-specific transcriptional inhibitor pifithrin-α or mitochondrial translocation inhibitor pifithrin-μ partially reversed solamargine-induced apoptosis.Solamargine activates the mitochondria-mediated apoptotic pathway in U2OS cells via both p53 transcription-dependent and -independent mechanisms. This compound may merit further investigation as a potential therapeutic agent for the treatment of cancer.Copyright © 2010 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21163271', 'no', 'no', 'solamargine', 6),
(21165567, 'Diniz MG, Borges ER, Pimenta FJ, De Mesquita Netto AC, De Marco L, Gomez RS, Gomes CC', 'Evidence of molecular alterations in the tumour suppressor gene WWOX in benign and malignant bone related lesions of the jaws.', 'Oncol Rep', '2011', 'Evidence of molecular alterations in the tumour suppressor gene WWOX in benign and malignant bone related lesions of the jaws. WWOX is a tumour suppressor gene altered in various human neoplasms. Deletion of WWOX is associated with bone metabolic defects and development of osteosarcoma in mice. We hypothesized that alterations of this gene are associated with the development of benign and malignant mesenchymal bone related lesions of the jaws. We investigated WWOX mRNA by nested reverse transcription-PCR and direct sequencing and quantitative real-time PCR in two osteosarcoma, two fibrosarcoma, eight ossifying fibroma and two fibrous dysplasia fresh samples. Malignancy was associated with a decreased WWOX mRNA expression. Aberrant transcription pattern was found in five samples; however, the relative quantification (RQ) of the WWOX mRNA in such lesions was not different from those carrying only the wild-type. We provide new evidence of WWOX alterations in osteosarcomas and demonstrate for the first time alterations of this gene in fibrosarcomas as well as in ossifying fibromas of the jaws.', 'http://www.ncbi.nlm.nih.gov/pubmed/21165567', 'yes', 'no', 'NA', 1),
(21166698, 'Fritsche-Guenther R, Noske A, Ungethüm U, Kuban RJ, Schlag PM, Tunn PU, Karle J, Krenn V, Dietel M, Sers C', 'De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signalling pathway.', 'Histopathology', '2010', 'De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signalling pathway. In osteosarcoma patients the development of metastases, often to the lungs, is the most frequent cause of death. The aim of this study was to elucidate the molecular mechanisms governing osteosarcoma development and dissemination and, thereby, to identify possible novel drug targets for improved treatment.Osteosarcoma samples were characterized using genome-wide microarrays: increased expression of the EphA2 receptor and its ligand EFNA1 was detected. In addition, increased expression of EFNB1, EFNB3 and EphA3 was suggested. Immunohistochemistry revealed an absence of EphA2 in normal bone, and de novo expression in osteosarcomas. EFNA1 was expressed in normal bone, but was significantly elevated in tumours. Further in vitro investigations on the functional role of EphA2 and EFNA1 showed that EFNA1 ligand binding induced increased tyrosine phosphorylation, receptor degradation and downstream mitogen-activated protein kinase (MAPK) activation. Interference with the MAPK pathway unravelled a potential autoregulatory loop governing mainly EFNA1 expression via the same pathway.Upregulation and de novo expression of ephrins in osteosarcomas are involved in oncogenic signalling and thus might stimulate osteosarcoma metastasis.© 2010 Blackwell Publishing Limited.', 'http://www.ncbi.nlm.nih.gov/pubmed/21166698', 'no', 'no', 'NA', 5),
(21166699, 'Fritsche-Guenther R, Gruetzkau A, Noske A, Melcher I, Schaser KD, Schlag PM, Kasper HU, Krenn V, Sers C', 'Therapeutic potential of CAMPATH-1H in skeletal tumours.', 'Histopathology', '2010', 'Therapeutic potential of CAMPATH-1H in skeletal tumours. CD 52 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that is expressed abundantly on all lymphocytes, monocytes, macrophages, eosinophils and in the male genital tract. To date, the physiological role of CD52 on lymphocytes has not been elucidated. However, an antibody directed to CD52 called CAMPATH-1H has been shown to be capable of depleting lymphocytes. The aim of this study was to analyse tissue and cell lines of non-neoplastic bone, cartilage and skeletal tumours for CD52 expression.The expression of CD52 mRNA and protein both in vivo and in vitro was detected. Malignant tumours showed higher CD52 expression compared to benign tumours, suggesting a role in the development and progression of bone tumours. Interestingly, immunohistochemistry and flow cytometry revealed that CD52 was expressed not only on the surface of tumour cells, but also in the cytoplasm. The results obtained in osteosarcoma cells showed that CAMPATH-1H leads to a complement-independent reduction of viable cells.CD52 is expressed in a variety of bone tumours and the in vitro studies presented herein suggest that CAMPATH-1H treatment might have therapeutic potential for osteosarcoma patients.© 2010 Blackwell Publishing Limited.', 'http://www.ncbi.nlm.nih.gov/pubmed/21166699', 'yes', 'no', 'NA', 1),
(21178508, 'Wang L, Park P, Zhang H, La Marca F, Claeson A, Valdivia J, Lin CY', 'BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line.', 'Cancer Biol Ther', '2011', 'BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Previously, based on high ALDH activity, we showed that cancer stem cells (CSCs) could be identified as ALDH(br) cells from an aggressive human osteosarcoma OS99-1 cell line. In this study, we evaluate the impact of BMP-2 on CSCs.Three types of BMP receptors were expressed in freshly sorted ALDH(br) cells. In vitro, growth of the sorted ALDH(br) cells was inhibited by BMP-2. Using RT-PCR analysis, BMP-2 was found to down-regulate the expression of embryonic stem cell markers Oct3/4, Nanog, and Sox-2, and up-regulate the transcription of osteogenic markers Runx-2 and Collagen Type I. In vivo, all animals receiving ALDH(br) cells treated with BMP-2 did not form significant tumors, while untreated ALDH(br) cells developed large tumor masses in NOD/SCID mice. Immunostaining confirmed few Ki-67 positive cells were present in the sections of tumor containing ALDH(br) cells treated with BMP-2. These results suggest that BMP-2 suppresses tumor growth by reducing the gene expression of tumorigenic factors and inducing the differentiation of CSCs in osteosarcoma. BMP-2 or BMP-2-mimetic drugs, if properly delivered to tumor and combined with traditional therapies, may therefore provide a new therapeutic option for treatment of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21178508', 'no', 'no', 'NA', 6),
(21192060, 'Seidinger AL, Mastellaro MJ, Paschoal Fortes F, Godoy Assumpção J, Aparecida Cardinalli I, Aparecida Ganazza M, Correa Ribeiro R, Brandalise SR, Dos Santos Aguiar S, Yunes JA', 'Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil.', 'Cancer', '2011', 'Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil. The inherited, low-penetrance arginine-to-histidine substitution at codon 337 (R337H) of the tumor protein 53 gene (TP53) is clustered in southeast Brazil (estimated frequency, 0.3%). Although its tumorigenic effect initially appeared to be tissue-specific, recent evidence suggests its association with a broader range of tumors. Therefore, the authors of this report investigated the spectrum of pediatric malignancies associated with the TP53 R337H mutation at a single referral institution in southeast Brazil.Genomic DNA samples from 493 children with malignancies were screened for the R337H mutation. Available tumor samples from carriers were investigated for loss of heterozygosity (LOH) and nuclear p53 accumulation. Clinical data were obtained from medical records.Sixty-five of 70 patients (93%) with adrenocortical tumors (ACTs), 9 of 13 patients (69%) with choroid plexus carcinoma (CPC), and 3 of 41 patients (7.3%) with osteosarcoma carried the mutation. The proportion of CPC to choroid plexus papilloma (CPP) was much higher than that reported elsewhere. Osteosarcoma in carriers had a significantly poorer outcome (P = .02). The mutation was not identified in patients who had acute lymphoblastic leukemia (ALL) (n = 187), recurrent ALL (n = 49), acute myeloid leukemia (n = 44), lymphoma (n = 30), non-CPC central nervous system tumors (n = 26), Ewing sarcoma (n = 25), or rhabdomyosarcoma (n = 8). Among the tumors that were available for analysis, LOH with retention of the mutant allele was confirmed in 21 of 21 ACTs, in 2 of 2 CPCs, and in 2 of 3 osteosarcomas that were positive for R337H. CPCs and osteosarcomas that were positive for R337H had marked nuclear accumulation of p53.The current findings demonstrated compellingly that the TP53 R337H mutation is associated not only with ACT but also with CPC and, to a lesser extent, with osteosarcoma, both of which are core-component tumors of the Li-Fraumeni syndrome.2010 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21192060', 'yes', 'no', 'NA', 1),
(21207222, 'Sharili AS, Allen S, Smith K, Hargreaves J, Price J, McGonnell I', 'Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy.', 'Tumour Biol', '2011', 'Expression of Snail2 in long bone osteosarcomas correlates with tumour malignancy. Snail2 is a marker of malignancy in epithelial tumours; however, in sarcomas, it is not known if this protein is present. Here we examine the expression of Snail2 in one type of sarcoma, osteosarcoma, and explore its relationship to tumour grade, subtype and anatomical location in cases of long bone and cranial bone osteosarcoma. Long bone osteosarcomas typically have a much greater metastatic capability and a poorer prognosis. We find that Snail2 is expressed in the three main subtypes of long bone osteosarcoma--osteoblastic, chondroblastic and fibroblastic. Regression analysis showed that Snail 2 expression was statistically correlated with tumour grade (p = 0.014) in all of these subtypes. Snail2 was only expressed in high-grade cranial bone osteosarcomas, suggesting a link between Snail2 expression and metastasis. This is the first time Snail2 has been associated with any sarcoma, and this study shows that Snail2 may be a useful prognostic marker for this disease.', 'http://www.ncbi.nlm.nih.gov/pubmed/21207222', 'yes', 'yes', 'NA', 1),
(21234653, 'Ji Y, Zhang YC, Pei LB, Shi LL, Yan JL, Ma XH', 'Anti-tumor effects of dihydroartemisinin on human osteosarcoma.', 'Mol Cell Biochem', '2011', 'Anti-tumor effects of dihydroartemisinin on human osteosarcoma. Dihydroartemisinin (DHA) exhibits antitumor activity against a wide spectrum of cancer cells. However, whether DHA has anti-tumor effect on human osteosarcoma cells remains unknown. This study aims to investigate the anti-tumor activity of DHA and the underlying mechanisms in human osteosarcoma cell lines with different p53 mutation statuses. Four human osteosarcoma cell lines were treated with different concentrations of DHA. Then, cell proliferation was determined by the CCK-8 viability assay; apoptosis and cell cycle progression were evaluated by flow cytometry; protein expression was analyzed by western blot assay; and NF-kB activity was examined by luciferase assay. The results demonstrated that DHA treatment could inhibit the proliferation of four osteosarcoma cell lines in a dose-dependent manner. P53 wild-type osteosarcoma cells were more sensitive to DHA. Moreover, the percentage of apoptotic cell and cell arrest in G₂/M phase was increased upon DHA treatment in a dose-dependent manner. Mechanistically, DHA activated caspase-3, caspase-8, and caspase-9; upregulated the expression of Bax, FAS, and cyclin D1; downregulated the expression of Bcl-2, Cdc25B, and cyclin B1; and inhibited the activity of NF-кB. In conclusion, DHA has significant anticancer effects against human osteosarcoma cells, which include induction of apoptosis and cell cycle arrest. The p53 gene may play a certain role in the DHA-induced human osteosarcoma apoptosis and cell cycle arrest. DHA is a novel anti-osteosarcoma drug candidate that merits further study.', 'http://www.ncbi.nlm.nih.gov/pubmed/21234653', 'no', 'no', 'dihydroartemisinin', 10),
(21236332, 'Kitz K, Windischhofer W, Leis HJ, Huber E, Kollroser M, Malle E', '15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species.', 'Free Radic Biol Med', '2011', '15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species. Prostaglandins (PGs), important modulators in bone biology, may also contribute to tumor formation and progression in human osteosarcoma. 15-Deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), a metabolite of PGD(2) and PPARγ-ligand, exerts a panel of biological activities via receptor-dependent and -independent mechanisms. As inducible cyclooxygenase-2 (Cox-2) is a candidate inflammatory marker in human osteosarcoma and a rate-limiting enzyme in PG biosynthesis, this study aimed at investigating intracellular redox status and signaling cascades leading to Cox-2 induction in human MG-63 osteosarcoma cells. 15d-PGJ(2) induced the accumulation of reactive oxygen species (ROS) that in turn may lead to upregulation of Cox-2 via two different routes in a PPARγ-independent manner. First, phosphorylation of p38 MAPK directly enhances Cox-2 expression by promoting mRNA stability. Second, 15d-PGJ(2) induces activation of epidermal growth factor receptors and downstream activation of Cox-2 via phosphorylation of p42/44 MAPK. Glutathione precursor molecules reversed enhanced ROS levels and Cox-2 expression. Functional activity of Cox-2 expression was tested by measurement of PGE(2) and PGF(2α). The synthetic compound 9,10-dihydro-15d-PGJ(2) lacking the α,β-unsaturated carbonyl group in the cyclopentenone ring did not exhibit the cellular responses observed with 15d-PGJ(2). We conclude that the electrophilic carbon atom of 15d-PGJ(2) is responsible for alterations in intracellular redox status and Cox-2 expression.Copyright © 2011 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21236332', 'no', 'no', 'NA', 5),
(21240382, 'Boulytcheva IV, Soloviev YN, Kushlinskii NE, Mahson AN', 'Expression of molecular markers in the tumor and survival prognosis in osteosarcoma.', 'Bull Exp Biol Med', '2010', 'Expression of molecular markers in the tumor and survival prognosis in osteosarcoma. Immunohistochemical study of p53, VEGF, Flt-1/VEGFR1 Ab-1, EGFR, HER-2/neu, Bax, and Cox-2 expression in osteosarcomas was carried out in 40 patients aged 16-70 years. Expression of p53 was detected in 27.5% tumors, VEGF in 15%, Flt-1/VEGFR1 Ab-1 in 97.5%, EGFR in 52.5%, HER-2/neu in 32.5%, Bax in 77.8%, and Cox-2 in 32.3% tumors. Multifactorial analysis showed that the expression of HER-2/neu (p=0.004), p53 (p=0.01), and Cox-2 (p=0.04) in osteosarcomas significantly correlated with unfavorable prognosis for overall survival, while HER-2/neu (p=0.02) and Cox-2 (p=0.003) with relapse-free survival. Analysis of HER-2/neu, p53, and Cox-2 expression in the primary tumor should be taken into consideration in the treatment of patients with osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21240382', 'yes', 'yes', 'NA', 7),
(21246613, 'Zhou R, Zhang Z, Zhao L, Jia C, Xu S, Mai Q, Lu M, Huang M, Wang L, Wang X, Jin D, Bai X', 'Inhibition of mTOR signaling by oleanolic acid contributes to its anti-tumor activity in osteosarcoma cells.', 'J Orthop Res', '2011', 'Inhibition of mTOR signaling by oleanolic acid contributes to its anti-tumor activity in osteosarcoma cells. Oleanolic acid (OA), a pentacyclic triterpenoid exhibits potent anti-tumor activity against many tumor cell lines. But the mechanisms through which OA inhibits osteosarcoma cells are not known. The mammalian target of rapamycin (mTOR) serves as a central regulator of cell growth, proliferation, survival, and metabolism by integrating intracellular and extracellular signals. In this study, we examined effects of OA on proliferation, cell cycle progression, apoptosis in osteosarcoma cells, and involvement of mTOR signaling in this process. OA inhibited cell proliferation and colony formation, induced G1 arrest in osteosarcoma MG63 and Saos-2 cells dose and time dependently. The protein level of cyclin D1, which plays critical role in G1 to S phase transition and servers as a downstream target of mTOR complex 1 (mTORC1) was down-regulated by OA. Phosphorylation of p70 ribosomal S6 kinase 1 (p70 S6K1) (T389) and S6 (S235/236), mediators of mTORC1 signaling in controlling protein translation and cell growth, was also inhibited by OA. Furthermore, OA inhibited phosphorylation of Akt, a pro-survival factor and substrate for mTORC2. Inactivation of Akt correlated with pro-apoptotic role of OA in osteosarcoma cells, as manifested by an increase in annexin V-FITC binding, cleavage of poly (ADP-ribose) polymerase (PARP) and activation of caspases 3. Our results suggest that OA is a promising agent for treatment of osteosarcoma and mTOR signaling may contribute to its anti-tumor effects on osteosarcoma cells.Copyright © 2011 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21246613', 'no', 'no', 'oleanolic acid', 7),
(21249357, 'Funovics PT, Edelhauser G, Funovics MA, Laux C, Berzaczy D, Kubista B, Kotz RI, Dominkus M', 'Pre-operative serum C-reactive protein as independent prognostic factor for survival but not infection in patients with high-grade osteosarcoma.', 'Int Orthop', '2011', 'Pre-operative serum C-reactive protein as independent prognostic factor for survival but not infection in patients with high-grade osteosarcoma. The purpose of this study was to investigate (a) whether pre-operative serum CRP is a predictor of survival in patients with high-grade osteosarcoma, (b) whether post-operative infection is a predictor of survival in these patients and (c) whether CRP is a predictor of post-operative infection, and especially deep prosthetic infection.In this retrospective single-centre study, pre-operative serum CRP levels in 79 patients (37 females, 42 males; average age, 18 years; mean follow-up, 46 months) undergoing resection of an osteosarcoma were correlated with clinical data and survival.The mean pre-operative serum CRP level of all 79 patients was 0.53 mg/dl (SD, 1.27 mg/dl). Patients dying of their underlying disease had significantly higher CRP levels compared to patients surviving throughout the follow-up period (1.09 mg/dl ± 2.02 mg/dl versus 0.32 mg/dl ± 0.75 mg/dl, respectively; p = 0.015). CRP levels were significantly correlated with survival (Pearson''s correlation coefficient = -0.25; p = 0.026) and histological subtype (Pearson''s correlation coefficient = -0.42; p < 0.001), but not with sex, age, histological response, tumour size or metastatic disease. In uni- and multivariate survival analysis, age, response to chemotherapy and serum CRP were associated with disease-specific survival. Patients with a CRP level over 1 mg/dl had a significantly lower disease-specific five-year survival of 36.7% compared to 73.8% in patients with normal CRP values (p = 0.020). Infection was not correlated with disease-specific survival. Pre-operative serum CRP levels were not correlated with post-operative infection or deep prosthetic infection.Pre-operative serum CRP seems to be an independent predictor of survival in patients with high-grade osteosarcoma. Further studies are needed to confirm these results on a large-scale basis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21249357', 'yes', 'yes', 'NA', 1),
(21266106, 'Park JH, Sihn CR, Lee YS, Lee SJ, Kim SH', 'Depletion of Neuroguidin/CANu1 sensitizes human osteosarcoma U2OS cells to doxorubicin.', 'BMB Rep', '2011', 'Depletion of Neuroguidin/CANu1 sensitizes human osteosarcoma U2OS cells to doxorubicin. Osteosarcoma is a primary bone cancer which occurs mainly in children. Neuroguidin/CANu1 is a nucleolar protein involved in the maintenance of ribosomal structure. In this study, we investigated the effect of Neuroguidin/CANu1 depletion on the response of osteosarcoma cells to doxorubicin. In normal circumstances, Neuroguidin/CANu1 is localized at nucleoli, which translocates to nuclear foci in the presence of doxorubicin. shRNA knockdown of Neuroguidin/CANu1 did not affect cell viability in the absence of doxorubicin, but led to enhanced cytotoxicity in doxorubicin-treated cells. Doxorubicin increased the population of apoptotic cells by 3-fold in Neuroguidin/CANu1-depleted cells compared to that in control cells. Depletion of Neuroguidin/CANu1 mRNA induced the expression of p21 and the cleavage of PARP, leading to increased caspase-3/7 activity. Together, these results suggest that Neuroguidin/CANu1 is required for maintaining cellular homeostasis and may contribute to the improved efficiency of chemotherapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/21266106', 'no', 'no', 'doxorubicin', 5),
(21283769, 'Matsunoshita Y, Ijiri K, Ishidou Y, Nagano S, Yamamoto T, Nagao H, Komiya S, Setoguchi T', 'Suppression of osteosarcoma cell invasion by chemotherapy is mediated by urokinase plasminogen activator activity via up-regulation of EGR1.', 'PLoS One', '2011', 'Suppression of osteosarcoma cell invasion by chemotherapy is mediated by urokinase plasminogen activator activity via up-regulation of EGR1. The cellular and molecular mechanisms of tumour response following chemotherapy are largely unknown. We found that low dose anti-tumour agents up-regulate early growth response 1 (EGR1) expression. EGR1 is a member of the immediate-early gene group of transcription factors which modulate transcription of multiple genes involved in cell proliferation, differentiation, and development. It has been reported that EGR1 act as either tumour promoting factor or suppressor. We therefore examined the expression and function of EGR1 in osteosarcoma.We investigated the expression of EGR1 in human osteosarcoma cell lines and biopsy specimens. We next examined the expression of EGR1 following anti-tumour agents treatment. To examine the function of EGR1 in osteosarcoma, we assessed the tumour growth and invasion in vitro and in vivo.Real-time PCR revealed that EGR1 was down-regulated both in osteosarcoma cell lines and osteosarcoma patients'' biopsy specimens. In addition, EGR1 was up-regulated both in osteosarcoma patient'' specimens and osteosarcoma cell lines following anti-tumour agent treatment. Although forced expression of EGR1 did not prevent osteosarcoma growth, forced expression of EGR1 prevented osteosarcoma cell invasion in vitro. In addition, forced expression of EGR1 promoted down-regulation of urokinase plasminogen activator, urokinase receptor, and urokinase plasminogen activity. Xenograft mice models showed that forced expression of EGR1 prevents osteosarcoma cell migration into blood vessels.These findings suggest that although chemotherapy could not prevent osteosarcoma growth in chemotherapy-resistant patients, it did prevent osteosarcoma cell invasion by down-regulation of urokinase plasminogen activity via up-regulation of EGR1 during chemotherapy periods.', 'http://www.ncbi.nlm.nih.gov/pubmed/21283769', 'yes', 'no', 'NA', 2),
(21286665, 'Holt SV, Brookes KE, Dive C, Makin GW', 'Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents.', 'Oncol Rep', '2011', 'Down-regulation of XIAP by AEG35156 in paediatric tumour cells induces apoptosis and sensitises cells to cytotoxic agents. Resistance to conventional chemotherapy is a major problem in several paediatric tumours. One explanation for this is that tumour cells are unable to engage apoptosis after cytotoxic drug-induced damage. Inhibitor of apoptosis proteins (IAPs) function by inhibiting both effector (9) and initiator (3 and 7) caspases. Repression of the widely expressed X-linked IAP (XIAP) by RNAi sensitises adult tumour cells to cytotoxics in vitro. Antisense oligonucleotide (ASO)-induced down-regulation of XIAP is effective at inducing cell death and delaying the growth of adult tumour cells as xenografts and these agents are currently in phase II clinical trials. The importance of XIAP in paediatric tumours has not been characterised but high expression correlates with poor survival in childhood AML. We have used the novel XIAP ASO (AEG35156) to evaluate the effects of down-regulation of XIAP in paediatric tumour cells. Here, we show that AEG35156 can down-regulate XIAP in a number of paediatric cell lines including models of osteosarcoma, rhabdomyosarcoma and Ewing''s sarcoma. Cell death assays demonstrated a higher proportion of dead cells after XIAP down-regulation by ASO and these cells displayed increased levels of cleaved caspase-3 and cleaved PARP, showing cell death was due to apoptosis. In long-term clonogenic assays, XIAP ASO sensitised 791T osteosarcoma cells to doxorubicin, etoposide and vincristine. The work presented here suggests that AEG35156, as a monotherapy or in combination with cytotoxic agents, may be of benefit in the treatment of paediatric tumours.', 'http://www.ncbi.nlm.nih.gov/pubmed/21286665', 'no', 'no', 'AEG35156', 3),
(21287529, 'Koshkina NV, Rao-Bindal K, Kleinerman ES', 'Effect of the histone deacetylase inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metastases.', 'Cancer', '2011', 'Effect of the histone deacetylase inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metastases. Patients with lung metastases from osteosarcoma (OS) have poor response to salvage therapy. Understanding the mechanisms involved in the metastatic process of OS may lead to new effective therapeutic approaches. The authors reported previously that up-regulation of the Fas receptor by transfecting OS cells with Fas plasmid inhibited the in vivo growth of metastases in the lungs.In the current study, the authors treated OS cells with the histone deacetylase inhibitor SNDX-275 and studied its cytotoxicity and its effect on Fas signaling in vitro and in vivo.Subtoxic doses of SNDX-275 were able to activate the Fas pathway in OS cells by increasing the expression of Fas messenger RNA; however, the increased expression was not always followed by increased levels of Fas receptor expression on the cell surface. The treatment of cells with a combination of SNDX-275 and Fas ligand (FasL) had a stronger cytotoxic effect on tested OS cells than either agent alone. Inhibition of the Fas pathway in cells by inhibition of the Fas-associated death domain (FADD) molecule eliminated this combination effect, indicating that activity of FADD is important for the efficacy of this agent in the FasL-expressing environment of the lungs. Intranasal administration of SNDX-275 in mice with OS lung metastases revealed that SNDX-275 may inhibit metastatic growth at a dose of 0.13 mg/kg, which is approximately 200-fold lower than the therapeutically effective oral dose reported previously.The current findings indicated that SNDX-275 can activate Fas signaling in OS cells in vitro and in vivo and that the administration of SDNX-275 by inhalation is feasible as a treatment for OS metastases and warrants its further investigation.Copyright © 2011 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21287529', 'no', 'no', 'SNDX-275', 3),
(21287809, 'Wang G, Rong J, Zhou Z, Duo J', 'Novel gene P28GANK confers multidrug resistance by modulating the expression of MDR-1, Bcl-2 and Bax in osteosarcoma cells.', 'Mol Biol (Mosk)', 'NA', 'Novel gene P28GANK confers multidrug resistance by modulating the expression of MDR-1, Bcl-2 and Bax in osteosarcoma cells. As previously reported, a novel gene P28GANK conferred a multidrug resistant phenotype in gastric cancer cells. The aim of this study was to explore the role of P28GANK in the development of multidrug resistance (MDR) in osteosarcoma cells. P28GANK gene was found to be overexpressed at the mRNA level and the protein level in a cisplatin induced MDR osteosarcoma cell line Saos-2/CDDP compared to its parent cell line Saos-2. Here, we transfected the osteosarcoma cell line Saos-2 with eukaryotic expression vector of P28GANK. In vitro drug sensitivity assay suggested that Saos-2-P28GANK cells conferred resistance to both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs. Blocking P28GANK expression in MDR osteosarcoma cells Saos-2/CDDP by P28GANK-specific small interfering RNA (siRNA) increased the cell sensitivity to various chemotherapeutic drugs. Flow cytometry examination suggested that P28GANK gene expression could suppress Adriamycin-induced apoptosis accompanied by decreased accumulation and increased release of Adriamycin. Semiquantitative RT-PCR, Western blot and Luciferase reporter assay suggested that P28GANK gene could significantly up-regulate the expression of MDR-1 and Bcl-2, transcription of the MDR-1 gene and down-regulate the expression of Bax. In addition, inhibition of P28GANK expression by RNA interference or P-gp inhibition could partially reverse P28GANK-mediated MDR. Taken together, our findings suggest that down-regulation of P28GANK gene expression could sensitize osteosarcoma cells to chemotherapeutic drugs by down-regulation of the MDR-1 and Bcl-2 and up-regulation of Bax gene expression, without altering the glutathione S-transferase activity, or intracellular glutathione content in osteosarcoma cells. Further study on biological function of P28GANK may be helpful for understanding MDR mechanism of osteosarcoma and developing a strategy for osteosarcoma treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/21287809', 'no', 'no', 'cisplatin', 4),
(21292304, 'Baumhoer D, Smida J, Specht K, Bink K, Quintanilla-Martinez L, Rosemann M, Siggelkow H, Nathrath WB, Atkinson MJ, Bielack S, Jundt G, Nathrath M', 'Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma.', 'Hum Pathol', '2011', 'Aberrant expression of the human epidermal growth factor receptor 2 oncogene is not a common feature in osteosarcoma. Human epidermal growth factor receptor 2 expression in osteosarcoma and its relationship to prognosis have been the subject of several conflicting reports, most of them relying on immunohistochemical studies. Because the urgent need of prognostic markers and effective new treatment options for osteosarcoma patients, we evaluated the role of human epidermal growth factor receptor 2 in 2 well-characterized sets of pretherapeutic osteosarcoma samples (46 paraffin-embedded and 46 fresh-frozen biopsy samples) using immunohistochemistry with 2 different antibodies [DAKO A0485 (Glostrup, Denmark) and Novocastra CB11 (Newcastle, UK)] as well as fluorescence in situ hybridization, real-time polymerase chain reaction, and SNP array analyses and correlated our findings with clinicopathological parameters. However, our study failed to detect unequivocal evidence of human epidermal growth factor receptor 2 gene amplification or overexpression of human epidermal growth factor receptor 2 messenger RNA or protein in any of the investigated tumors. Only in a small subset of samples, a moderate increase in messenger RNA levels (13.6%) or focal membranous immunoreactivity (8.7%; A0485) was detected but did not correlate with survival or response to chemotherapy. Cytoplasmic staining was identified more frequently (63%; CB11) but again did not show any association with clinicopathological parameters. In conclusion, our study does not support a role for human epidermal growth factor receptor 2 as a prognostic marker in osteosarcoma.Copyright © 2011 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21292304', 'yes', 'no', 'NA', 1),
(21297379, 'Moon MH, Jeong JK, Seo JS, Seol JW, Lee YJ, Xue M, Jackson CJ, Park SY', 'Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells via death receptor 5 upregulation.', 'Exp Mol Med', '2011', 'Bisphosphonate enhances TRAIL sensitivity to human osteosarcoma cells via death receptor 5 upregulation. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily of cytokines, is one of the most promising candidates for cancer therapeutics. However, many osteosarcomas are resistant to TRAIL. Bisphosphonates are very effective in the treatment of bone problems associated with malignancies; the antitumor effects are due to the inhibition of protein prenylation that is essential for cell function and survival. The purpose of this study was to determine the effects of bisphosphonates on TRAIL-resistant MG 63 human osteosarcoma cells. The cells showed no response to TRAIL alone; however, pre-treatment with bisphosphonates significantly increased TRAIL-mediated apoptosis and cellular activation of caspase-3. Bisphosphonates significantly induced mRNA and protein expression of the TRAIL receptor, DR5. Bisphosphonates induced protein unprenylation in MG 63 cells; in addition, co-treatment with TRAIL also significantly increased protein unprenylation. Blocking of protein unprenylation using geranylgeraniol attenuated the cellular responses, including cell apoptosis and protein unprenylation induced by bisphosphonates and TRAIL. This is the first study to demonstrate that bisphosphonates markedly enhanced TRAIL-induced apoptosis in human osteosarcoma cells. These findings suggest that bisphosphonates may be a new and effective anticancer treatment with TRAIL proteins for TRAIL-resistant cancer cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21297379', 'no', 'no', 'biphosphonate', 1),
(21311599, 'Wu Z, Min L, Chen D, Hao D, Duan Y, Qiu G, Wang Y', 'Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma.', 'PLoS One', '2011', 'Overexpression of BMI-1 promotes cell growth and resistance to cisplatin treatment in osteosarcoma. BMI-1 is a member of the polycomb group of genes (PcGs), and it has been implicated in the development and progression of several malignancies, but its role in osteosarcoma remains to be elucidated.In the present study, we found that BMI-1 was overexpressed in different types of osteosarcomas. Downregulation of BMI-1 by lentivirus mediated RNA interference (RNAi) significantly impaired cell viability and colony formation in vitro and tumorigenesis in vivo of osteosarcoma cells. BMI-1 knockdown sensitized cells to cisplatin-induced apoptosis through inhibition of PI3K/AKT pathway. Moreover, BMI-1-depletion-induced phenotype could be rescued by forced expression of BMI-1 wobble mutant which is resistant to inhibition by the small interfering RNA (siRNA).These findings suggest a crucial role for BMI-1 in osteosarcoma pathogenesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21311599', 'yes', 'no', 'cisplatin', 1),
(21312266, 'Fromigue O, Hamidouche Z, Vaudin P, Lecanda F, Patino A, Barbry P, Mari B, Marie PJ', 'CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis.', 'J Bone Miner Res', '2011', 'CYR61 downregulation reduces osteosarcoma cell invasion, migration, and metastasis. Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and the poor survival rate for patients. We showed previously that the HMGCoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor statin exhibits antitumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify Cyr61 as a new target of statins. Transcriptome and molecular analyses revealed that statins downregulate Cyr61 expression in human and murine osteosarcoma cells. Cyr61 silencing in osteosarcoma cell lines enhanced cell death and reduced cell migration and cell invasion compared with parental cells, whereas Cyr61 overexpression had opposite effects. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients. Tissue microarray analysis revealed that Cyr61 protein expression was higher in human osteosarcoma than in normal bone tissue and was further increased in metastatic tissues. Finally, tumor behavior and metastasis occurrence were analyzed by intramuscular injection of modified osteosarcoma cells into BALB/c mice. Cyr61 overexpression enhanced lung metastasis development, whereas cyr61 silencing strongly reduced lung metastases in mice. The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma.Copyright © 2011 American Society for Bone and Mineral Research.', 'http://www.ncbi.nlm.nih.gov/pubmed/21312266', 'yes', 'yes', 'statin', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(21321933, 'Cifuentes M, García MA, Arrabal PM, Martínez F, Yañez MJ, Jara N, Weil B, Domínguez D, Medina RA, Nualart F', 'Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells.', 'J Cell Physiol', '2011', 'Insulin regulates GLUT1-mediated glucose transport in MG-63 human osteosarcoma cells. Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. Because cancer cells utilize glucose as their primary energy substrate, the expression and regulation of glucose transporters (GLUT) may be important in tumor development and progression. GLUT expression has not been studied previously in human osteosarcoma cell lines. Furthermore, although insulin and insulin-like growth factor (IGF-I) play an important role in cell proliferation and tumor progression, the role of these hormones on GLUT expression and glucose uptake, and their possible relation to osteosarcoma, have also not been studied. We determined the effect of insulin and IGF-I on GLUT expression and glucose transport in three well-characterized human osteosarcoma cell lines (MG-63, SaOs-2, and U2-Os) using immunocytochemical, RT-PCR and functional kinetic analyses. Furthermore we also studied GLUT isoform expression in osteosarcoma primary tumors and metastases by in situ hybridization and immunohistochemical analyses. RT-PCR and immunostaining show that GLUT1 is the main isoform expressed in the cell lines and tissues studied, respectively. Immunocytochemical analysis shows that although insulin does not affect levels of GLUT1 expression it does induce a translocation of the transporter to the plasma membrane. This translocation is associated with increased transport of glucose into the cell. GLUT1 is the main glucose transporter expressed in osteosarcoma, furthermore, this transporter is regulated by insulin in human MG-63 cells. One possible mechanism through which insulin is involved in cancer progression is by increasing the amount of glucose available to the cancer cell.Copyright © 2011 Wiley Periodicals, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/21321933', 'yes', 'no', 'NA', 3),
(21331449, 'Zhao W, Zhou SF, Zhang ZP, Xu GP, Li XB, Yan JL', 'Gambogic acid inhibits the growth of osteosarcoma cells in vitro by inducing apoptosis and cell cycle arrest.', 'Oncol Rep', '2011', 'Gambogic acid inhibits the growth of osteosarcoma cells in vitro by inducing apoptosis and cell cycle arrest. The natural product gambogic acid (GA) has been demonstrated to be a promising chemotherapeutic drug for some cancers because of its ability to induce apoptosis and cell cycle arrest. Until now, no studies have looked at the role of GA in osteosarcoma. In this study, we observed the effects of GA on the growth and apoptosis of osteosarcoma cells in vitro. We found that GA treatment inhibits the proliferation of osteosarcoma cells by inducing cell cycle arrest. Moreover, we found that GA induces apoptosis in MG63, HOS and U2OS cells. Furthermore, we showed that GA treatment elevates the Bax/Bcl-2 ratio. GA mediated the G0/G1 phase arrest in U2OS cells; this arrest was associated with a decrease in phospho-GSK3-β (Ser9) and the expression of cyclin D1. Similarly, in MG63 cells, GA mediated G2/M cell cycle arrest, which was associated with a decrease in phospho-cdc2 (Thr 161) and cdc25B. Overall, our findings suggest that GA may be an effective anti-osteosarcoma drug because of its capability to inhibit proliferation and induce apoptosis of osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21331449', 'no', 'no', 'gambogic acid', 6),
(21336260, 'Dujardin F, Binh MB, Bouvier C, Gomez-Brouchet A, Larousserie F, Muret Ad, Louis-Brennetot C, Aurias A, Coindre JM, Guillou L, Pedeutour F, Duval H, Collin C, de Pinieux G', 'MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone.', 'Mod Pathol', '2011', 'MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone. Low-grade osteosarcoma is a rare malignancy that may be subdivided into two main subgroups on the basis of location in relation to the bone cortex, that is, parosteal osteosarcoma and low-grade central osteosarcoma. Their histological appearance is quite similar and characterized by spindle cell stroma with low-to-moderate cellularity and well-differentiated anastomosing bone trabeculae. Low-grade osteosarcomas have a simple genetic profile with supernumerary ring chromosomes comprising amplification of chromosome 12q13-15, including the cyclin-dependent kinase 4 (CDK4) and murine double-minute type 2 (MDM2) gene region. Low-grade osteosarcoma can be confused with fibrous and fibro-osseous lesions such as fibromatosis and fibrous dysplasia on radiological and histological findings. We investigated MDM2-CDK4 immunohistochemical expression in a series of 72 low-grade osteosarcomas and 107 fibrous or fibro-osseous lesions of the bone or paraosseous soft tissue. The MDM2-CDK4 amplification status of low-grade osteosarcoma was also evaluated by comparative genomic hybridization array in 18 cases, and the MDM2 amplification status was evaluated by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction in 31 cases of benign fibrous and fibro-osseous lesions. MDM2-CDK4 immunostaining and MDM2 amplification by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction were investigated in a control group of 23 cases of primary high-grade bone sarcoma, including 20 conventional high-grade osteosarcomas, two pleomorphic spindle cell sarcomas/malignant fibrous histiocytomas and one leiomyosarcoma. The results showed that MDM2 and/or CDK4 immunoreactivity was present in 89% of low-grade osteosarcoma specimens. All benign fibrous and fibro-osseous lesions and the tumors of the control group were negative for MDM2 and CDK4. These results were consistent with the MDM2 and CDK4 amplification results. In conclusion, immunohistochemical expression of MDM2 and CDK4 is specific and provides sensitive markers for the diagnosis of low-grade osteosarcomas, helping to differentiate them from benign fibrous and fibro-osseous lesions, particularly in cases with atypical radio-clinical presentation and/or limited biopsy samples.', 'http://www.ncbi.nlm.nih.gov/pubmed/21336260', 'yes', 'yes', 'NA', 2),
(21340507, 'Onimoe GI, Liu A, Lin L, Wei CC, Schwartz EB, Bhasin D, Li C, Fuchs JR, Li PK, Houghton P, Termuhlen A, Gross T, Lin J', 'Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice.', 'Invest New Drugs', '2012', 'Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21340507', 'no', 'no', 'LLL12|FLLL32', 1),
(21345075, 'Wozniak A, Fryer A, Grimer R, Mc Dowell H', 'Multiple malignancies in a child with de novo TP53 mutation.', 'Pediatr Hematol Oncol', '2011', 'Multiple malignancies in a child with de novo TP53 mutation. The authors present the case of an 8.5-year-old boy diagnosed with embryonal rhabdomyosarcoma of the infratemporal fossa at 21 months old. Five years later he developed an osteosarcoma of the tibia, for which he was treated with standard chemotherapy and resection. Soon after completing this treatment, ptosis of the right eye developed. A mass in the cavernous sinus was found, interpreted as an osteogenic metastatsis, although a third primary tumor could not be ruled out. Molecular genetic investigation revealed a de novo germline TP53 mutation, and heralded an aggressive clinical progression of multiple malignancies in a child.', 'http://www.ncbi.nlm.nih.gov/pubmed/21345075', 'yes', 'no', 'NA', 1),
(21370405, 'Lee JA, Jung JS, Kim DH, Lim JS, Kim MS, Kong CB, Song WS, Cho WH, Jeon DG, Lee SY, Koh JS', 'RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma.', 'Pediatr Blood Cancer', '2011', 'RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. The receptor activator of nuclear factor κB ligand (RANKL/TNFSF11) is expressed in metastatic bone cancer cells and has been suggested to play a key role in cell migration and metastatic behavior. We determined whether RANKL expression is correlated to clinical behavior of localized, high-grade osteosarcoma.This retrospective, immunohistochemical study was performed using materials obtained from 40 patients treated at Korea Cancer Center Hospital between 1995 and 2007. Prechemotherapy biopsy samples were stained for RANKL and correlations between RANKL expression and clinical characteristics and outcomes were evaluated. Staining was interpreted in a semiquantitative manner using an intensity based scoring system.Thirty cases (75.0%) stained positively for RANKL; 15 (50.0%) had a high RANKL score (≥ 4) and the other 15 a low RANKL score (≤3). RANKL expression and RANKL scores were not related to age, sex, tumor location, tumor volume, or pathologic subtype. However, RANKL expression was related to a poor response to preoperative chemotherapy (P = 0.03) and a high RANKL score was associated with inferior survival. The 5-year event-free survival of patients with RANKL score ≥4 was 17.8 ± 10.5%, which was far worse than those with RANKL scores 1-3 or 0 (50.0 ± 15.8%, 56.0 ± 13.7%, respectively, P = 0.02).The RANKL-RANK-OPG axis might be a promising target for the treatment of osteosarcoma, but further studies are needed to verify our data in a larger cohort.Copyright © 2011 Wiley-Liss, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/21370405', 'yes', 'yes', 'NA', 1),
(21375766, 'Zhao Q, Wang C, Zhu J, Wang L, Dong S, Zhang G, Tian J', 'RNAi-mediated knockdown of cyclooxygenase2 inhibits the growth, invasion and migration of SaOS2 human osteosarcoma cells: a case control study.', 'J Exp Clin Cancer Res', '2011', 'RNAi-mediated knockdown of cyclooxygenase2 inhibits the growth, invasion and migration of SaOS2 human osteosarcoma cells: a case control study. Cyclooxygenase2 (COX-2), one isoform of cyclooxygenase proinflammatory enzymes, is responsible for tumor development, invasion and metastasis. Due to its role and frequent overexpression in a variety of human malignancies, including osteosarcoma, COX-2 has received considerable attention. However, the function of COX-2 in the pathogenesis of cancer is not well understood. We examined the role of COX-2 in osteosarcoma.We employed lentivirus mediated-RNA interference technology to knockdown endogenous gene COX-2 expression in human osteosarcoma cells (SaOS2) and analyzed the phenotypical changes. The effect of COX-2 treatment on the proliferation, cell cycle, invasion and migration of the SaOS2 cells were assessed using the MTT, flow cytometry, invasion and migration assays, respectively. COX-2, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) mRNA and protein expression were detected by RT-PCR and western blotting.Our results indicate that a decrease of COX-2 expression in human osteosarcoma cells significantly inhibited the growth, decreased the invasion and migration ability of SaOS2 cells. In addition, it also reduced VEGF, EGF and bFGF mRNA and protein expression.The COX-2 signaling pathway may provide a novel therapeutic target for the treatment of human osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21375766', 'no', 'no', 'NA', 4),
(21378337, 'Sasaki K, Hitora T, Nakamura O, Kono R, Yamamoto T', 'The role of MAPK pathway in bone and soft tissue tumors.', 'Anticancer Res', '2011', 'The role of MAPK pathway in bone and soft tissue tumors. Expression of mitogen-activated protein kinase (MAPK) signaling and its role in cell proliferation of the bone malignancies, osteosarcoma (OS) and malignant fibrous histiocytoma (MFH) were investigated.Gene expression and protein levels of RAF1 and MEK1/2 in 6 human sarcoma cell lines and 7 surgically obtained OS specimens were assessed by RT-PCR and immunohistochemistry, respectively. MEK inhibitor, U0126 [1,4-diamino-2,3-dicyano-1,4-bis (2-aminophynyltio) butadiene], was used for cell proliferation assays.RAF1 and MEK 1/2 mRNA was detected in all cell lines and OS specimens. RAF1, MEK 1/2 and p-MEK protein was also expressed in the cells, as was MEK1/2 in OS specimens. Treatment with U0126 resulted in dose- and time-dependent inhibition of cell proliferation and suppression of p-ERK expression, opposite to promotion of p-MEK.U0126 blocks MAPK signaling and decreases cell proliferation in OS and MFH. Thus, selective MAPK inhibitors might be therapeutically advantageous in the treatment of bone and soft tissue sarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/21378337', 'yes', 'no', 'U0126', 3),
(21387396, 'Liu X, Choy E, Hornicek FJ, Yang S, Yang C, Harmon D, Mankin H, Duan Z', 'ROCK1 as a potential therapeutic target in osteosarcoma.', 'J Orthop Res', '2011', 'ROCK1 as a potential therapeutic target in osteosarcoma. Osteosarcoma is the most common primary malignancy of bone. Patients with localized disease are routinely treated with surgery and chemotherapy. Unfortunately, many of these patients eventually relapse even after high-dose pre- and postoperative chemotherapy. Upon recurrence of the tumor locally or distantly, they have limited treatment options that are usually unsuccessful. Our prior studies screening lentiviral shRNA libraries, searching for kinases involved in osteosarcoma cell growth and proliferation have identified the Rho-associated coiled-coil containing protein kinase 1 (ROCK1) as a possible hit. We show in this study that ROCK1 is highly expressed in various tumor cell lines and tumor tissues from osteosarcoma patients. ROCK1 knockdown by synthetic siRNA decreases cell proliferation, viability and induces apoptosis in osteosarcoma cell lines KHOS and U-2OS. Finally, we established the relationship between expression levels of ROCK1 and clinical prognosis in osteosarcoma patients by using immunohistochemistry. There were significant differences in overall survival between cohorts of patients with ROCK1 levels categorized as high-staining, moderate-staining, and low-staining. High levels of ROCK1 were associated with poor outcomes in clinical osteosarcoma. These findings suggest that knockdown of ROCK1 inhibits proliferation and induces apoptosis in osteosarcoma cell lines. ROCK1 may be a promising therapeutic target for the treatment of osteosarcoma patients.Copyright © 2011 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21387396', 'yes', 'no', 'NA', 1),
(21399492, 'Liu X, Choy E, Harmon D, Yang S, Yang C, Mankin H, Hornicek FJ, Duan Z', 'Inhibition of polo-like kinase 1 leads to the suppression of osteosarcoma cell growth in vitro and in vivo.', 'Anticancer Drugs', '2011', 'Inhibition of polo-like kinase 1 leads to the suppression of osteosarcoma cell growth in vitro and in vivo. Osteosarcoma is the most common type of primary bone cancer in children and adolescents. Treatment options for osteosarcoma may include surgery, chemotherapy, and radiotherapy. Unfortunately, many patients eventually relapse, resulting in an unsatisfactory outcome. The serine/threonine-specific polo-like kinase 1 (PLK1) is a kinase that plays an important role in mitosis and the maintenance of genomic stability. PLK1 has been found to be highly expressed in the malignant cells of osteosarcoma. Here, we describe the in-vitro and in-vivo effects of BI 2536, a small-molecule inhibitor of PLK1, which through inhibiting PLK1 enzymatic activity, causes mitotic arrest and eventually induces cancer cell apoptosis. In this study, we show that the PLK1 inhibitor, BI 2536, inhibits proliferation and induces apoptosis in two-dimensional and three-dimensional cultures of osteosarcoma cell lines, KHOS and U-2OS. A proliferation assay performed both in two-dimensional and three-dimensional culture showed that the growth of both cell lines was inhibited by BI 2536. Cell cycle analysis showed that the cells treated with BI 2536 were mainly arrested in the G2/M phase. Immunofluorescence and western blotting analysis confirmed that the administration of BI 2536 led to significant decrease of PLK1 and Mcl-1 protein expression levels in dose-dependent and time-dependent manners. Furthermore, BI 2536-induced apoptosis in the osteosarcoma cell lines was shown by poly (ADP-ribose) polymerase cleavage and caspase assay. Finally, in mouse osteosarcoma xenografts, BI 2536-treated mice had significantly smaller tumors compared with the control mice. These findings offer evidence of the potential role for targeting PLK1 in osteosarcoma therapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/21399492', 'no', 'no', 'BI 2536', 1),
(21411701, 'Kubo T, Shimose S, Matsuo T, Fujimori J, Arihiro K, Ochi M', 'Interferon-α/β receptor as a prognostic marker in osteosarcoma.', 'J Bone Joint Surg Am', '2011', 'Interferon-α/β receptor as a prognostic marker in osteosarcoma. A large-scale randomized trial of adjuvant interferon-α therapy for patients with osteosarcoma has been initiated as a joint protocol by the European and American Osteosarcoma Study Group. Because the expression of functional interferon-α/β receptor is necessary for interferon-α agents to interact with osteosarcoma cells, we examined the expression of interferon-α/β receptor in a series of osteosarcoma specimens.Forty patients with high-grade resectable osteosarcoma, from whom surgical specimens had been obtained at the time of biopsy, were included in this retrospective study. Biopsy specimens were immunohistochemically stained with anti-interferon-α/β receptor antibodies. Survival was estimated with the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis to determine the independent prognostic factors. Furthermore, we used Holm and Benjamini-Hochberg procedures to adjust for multiple comparisons in setting the level of significance. The median follow-up period was five years and two months (range, four to 195 months).The expression of interferon-α/β receptor was positive in eighteen (45%) of the forty patients with high-grade osteosarcoma. American Joint Committee on Cancer surgical stage IIA, a good histologic response to chemotherapy, and expression of interferon-α/β receptor correlated significantly with better disease-free survival (p < 0.05). Multivariate analysis showed that interferon-α/β receptor expression alone retained its power to predict an improved prognosis (p = 0.042). There were no significant variables after corrections for multiple comparisons.Interferon-α/β receptor may be a useful marker for assessing tumor prognosis in patients with osteosarcoma and may play an important role in tumor progression. These findings are encouraging and support the ongoing clinical trials of adjuvant interferon-α therapy by the multinational Osteosarcoma Study Group. Our pilot study was based on a small sample size, and larger trials are needed to confirm this finding.Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence.', 'http://www.ncbi.nlm.nih.gov/pubmed/21411701', 'yes', 'yes', 'NA', 2),
(21416580, 'Ługowska I, Woźniak W, Klepacka T, Michalak E, Szamotulska K', 'A prognostic evaluation of vascular endothelial growth factor in children and young adults with osteosarcoma.', 'Pediatr Blood Cancer', '2011', 'A prognostic evaluation of vascular endothelial growth factor in children and young adults with osteosarcoma. The potential role of VEGF in osteosarcoma has been evaluated in several studies. The majority of them included heterogeneous and limited series of patients, giving conflicting results. The aim of presented study is to evaluate the prognostic role of VEGF-A in biopsy samples of clinically homogeneous group of osteosarcoma patients with at least 5 years of follow up.VEGF-A was assessed immunohistochemically in the pre-treatment biopsy samples of 91 patients (mean age 14 years; range, 4-23 years) with primary, high-grade, non-metastatic osteosarcoma localized in extremities. The survival of each patient was assessed after at least 5-year follow-up period.VEGF-A over 50% of positive tumor cells was observed in 39% of cases and was linked to patients age below 14-year old (P = 0.025) and tumor size more than 8 cm (P = 0.054). VEGF-A was associated with a significantly decreased both overall survival (P = 0.006) and progression-free survival (P = 0.011). In the Cox proportional hazard model it was confirmed that VEGF-A expression in the biopsy samples was an independent prognostic factor of unfavorable survival in osteosarcoma (HR 2.51; 95% CI: 1.12-5.66).The expression of VEGF-A in the biopsy sample is the potential marker for predicting the course and outcome of osteosarcoma.Copyright © 2011 Wiley-Liss, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/21416580', 'yes', 'yes', 'NA', 1),
(21421073, 'Nikitovic D, Chalkiadaki G, Berdiaki A, Aggelidakis J, Katonis P, Karamanos NK, Tzanakakis GN', 'Lumican regulates osteosarcoma cell adhesion by modulating TGFβ2 activity.', 'Int J Biochem Cell Biol', '2011', 'Lumican regulates osteosarcoma cell adhesion by modulating TGFβ2 activity. Human osteosarcoma cell lines were recently shown to express and secrete the small leucine rich proteoglycan (SLRP) lumican, with the ability to regulate the growth and motility of these cells. In this study, lumican-deficient Saos 2 cells were demonstrated to have increased adhesive capability onto fibronectin (FN) (p≤0.01). Upon neutralization of endogenous transforming growth factor β2 (TGF-β2) activity, no difference in the ability of lumican siRNA-transfected and scramble siRNA-transfected Saos 2 cells to adhere onto FN was detected (p=NS). Exogenous TGF-β2 was shown to stimulate Saos 2 cell adhesion to FN (p≤0.01). These results therefore, suggest that the inverse correlation existing between lumican expression and Saos 2 cell adhesion is dependent on active TGF-β2 signaling. Furthermore, the significant increase in Smad 2 activation present in lumican-deficient cells (p≤0.01) was annulled in the presence of the anti-TGF-β2 peptide, demonstrating that lumican is an upstream regulator of the TGF-β2/Smad 2 signaling cascade. Crucial to FN-dependent adhesion, β1 integrin expression and pFAK activation were likewise identified as downstream TGF-β2 effectors regulated by lumican expression. In conclusion, this study demonstrates a novel out-in signaling circuit in human osteosarcoma cells: secreted to extracellular matrix lumican is an endogenous inhibitor of TGF-β2 activity, resulting in downstream effector modulation including pSmad 2, integrin β1 and pFAK to regulate osteosarcoma adhesion.Copyright © 2011 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21421073', 'no', 'no', 'NA', 6),
(21424568, 'Cui Q, Jiang W, Guo J, Liu C, Li D, Wang X, Zeng Y', 'Relationship between hypermethylated MGMT gene and osteosarcoma necrosis rate after chemotherapy.', 'Pathol Oncol Res', '2011', 'Relationship between hypermethylated MGMT gene and osteosarcoma necrosis rate after chemotherapy. To investigate the relativity of MGMT(O-6-methylguanine-DNA methyltransferase) gene methylation from patients with protein expression and osteosarcoma necrosis rate after chemotherapy. Fifty-one oteosarcoma tissues were collected, Methylation of MGMT gene promoter was detected by methylation-specific PCR method, and protein expression of MGMT was examined by immunohistochemistry procedure, the relationship between methylated MGMT gene expression and patients response to chemotherapy was analyzed. The positive ratio of methylation MGMT gene promoter in 51 patients was 23.5% (12 in 51). Negative percentage of protein expression of MGMT was 27.5% (14 in 51). It seemed that methylation of MGMT gene in osteosarcoma tissues had no evident relationship with the patient''s age, sexuality, and the size and type of neoplasms, etc. The necrosis rates of methylated MGMT of osteosarcoma (tumor grade from I to IV) were 0 (0/51), 3.9% (2/51), 5.9% (3/51), 13.7% (7/51), respectively. In contrast, the necrosis rates of unmethylated MGMT of osteosarcoma (tumor grade from I to IV) were 45.1% (23/51), 25.5% (13/51), 3.9% (2/51), 2.0% (1/51), respectively. It suggest that methylated and unmethylated MGMT gene of osteosarcoma have significant difference in protein expression. The unmethylated MGMT gene has higher positive protein expression (u = -4.92, P < 0.001). Methylation of MGMT gene has higher tumor necrosis rate in osteosarcoma patients. Methylation in MGMT promoter may be important for judging the effect of chemotherapy in Osteosarcoma patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/21424568', 'yes', 'no', 'NA', 1),
(21427707, 'Osaki M, Takeshita F, Sugimoto Y, Kosaka N, Yamamoto Y, Yoshioka Y, Kobayashi E, Yamada T, Kawai A, Inoue T, Ito H, Oshimura M, Ochiya T', 'MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression.', 'Mol Ther', '2011', 'MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression. Pulmonary metastases are the main cause of death in patients with osteosarcoma, however, the molecular mechanisms of metastasis are not well understood. To detect lung metastasis-related microRNA (miRNA) in human osteosarcoma, we compared parental (HOS) and its subclone (143B) human osteosarcoma cell lines showing lung metastasis in a mouse model. miR-143 was the most downregulated miRNA (P < 0.01), and transfection of miR-143 into 143B significantly decreased its invasiveness, but not cell proliferation. Noninvasive optical imaging technologies revealed that intravenous injection of miR-143, but not negative control miRNA, significantly suppressed lung metastasis of 143B (P < 0.01). To search for miR-143 target mRNA in 143B, microarray analyses were performed using an independent RNA pool extracted by two different comprehensive miR-143-target mRNA collecting systems. Western blot analyses revealed that MMP-13 was mostly protein downregulated by miR-143. Immunohistochemistry using clinical samples clearly revealed MMP-13-positive cells in lung metastasis-positive cases, but not in at least three cases showing higher miR-143 expression in the no metastasis group. Taken together, these data indicated that the downregulation of miR-143 correlates with the lung metastasis of human osteosarcoma cells by promoting cellular invasion, probably via MMP-13 upregulation, suggesting that miRNA could be used to develop new molecular targets for osteosarcoma metastasis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21427707', 'no', 'no', 'NA', 2),
(21436869, 'Yan T, Tang G, Ren T, Shen D, Sun K, Liang W, Guo W', 'RNAi-mediated COPS3 gene silencing inhibits metastasis of osteogenic sarcoma cells.', 'Cancer Gene Ther', '2011', 'RNAi-mediated COPS3 gene silencing inhibits metastasis of osteogenic sarcoma cells. Metastatic disease is the primary cause of mortality among patients with osteogenic sarcoma (OGS). In this study, we aimed to identify the relationship of COPS3 gene expression to metastasis. Immunohistochemical staining for COPS3 was performed on 65 OGS samples (37 without and 28 with metastatic disease); 18.9% (7/37) of specimens from patients with no metastasis and 57.1% (16/28) of specimens from patients with metastasis showed intense staining of COPS3. Comparison of COPS3 expression between a poorly metastatic osteosarcoma cell line (SAOS-2) and highly metastatic osteosarcoma cell line (HOS) showed stronger expression of COPS3 in HOS cells. Inhibiting COPS3 function by siRNA resulted in reduced proliferation and migration of HOS cells. Inhibition of COPS3 gene downregulated expression of the MAPK signaling pathway, which has an important role in metastasis of OGS. Our results suggested that overexpression of the COPS3 gene might have important roles in metastasis of osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21436869', 'yes', 'no', 'NA', 1),
(21440986, 'Lee DH, Thoennissen NH, Goff C, Iwanski GB, Forscher C, Doan NB, Said JW, Koeffler HP', 'Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma.', 'Cancer Lett', '2011', 'Synergistic effect of low-dose cucurbitacin B and low-dose methotrexate for treatment of human osteosarcoma. We investigated the use of cucurbitacin B, a plant-derived tetracyclic triterpenoid, as a single agent or in combination with methotrexate (MTX) for human osteosarcoma (OS) treatment. Cucurbitacin B showed antiproliferative activity against seven human OS cell lines in vitro accompanying G2/M cell cycle arrest, apoptosis, and inhibition of ERK, Akt, and mTOR proteins. Cucurbitacin B in combination with MTX synergistically inhibited OS cell growth in vitro. Low-dose cucurbitacin B (LD-CuB, 0.5 mg/kg body weight) or low-dose MTX (LD-MTX, 150 mg/kg) failed to decrease the size of human OS xenografts in nude mice. However, combined therapy at identical concentrations inhibited tumor growth by 62% vs. LD-CuB and 81% vs. LD-MTX (p<0.001). Strikingly, the effect persisted even when the dose of MTX was decreased by two thirds (VLD-MTX, 50 mg/kg). In conclusion, cucurbitacin B alone or in combination with MTX shows promising antiproliferative activity against human OS.Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21440986', 'no', 'no', 'cucurbitacin B', 3),
(21443800, 'Fossey SL, Bear MD, Lin J, Li C, Schwartz EB, Li PK, Fuchs JR, Fenger J, Kisseberth WC, London CA', 'The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines.', 'BMC Cancer', '2011', 'The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines. Curcumin is a naturally occurring phenolic compound shown to have a wide variety of antitumor activities; however, it does not attain sufficient blood levels to do so when ingested. Using structure-based design, a novel compound, FLLL32, was generated from curcumin. FLLL32 possesses superior biochemical properties and more specifically targets STAT3, a transcription factor important in tumor cell survival, proliferation, metastasis, and chemotherapy resistance. In our previous work, we found that several canine and human osteosarcoma (OSA) cell lines, but not normal osteoblasts, exhibit constitutive phosphorylation of STAT3. Compared to curcumin, we hypothesized that FLLL32 would be more efficient at inhibiting STAT3 function in OSA cells and that this would result in enhanced downregulation of STAT3 transcriptional targets and subsequent death of OSA cells.Human and canine OSA cells were treated with vehicle, curcumin, or FLLL32 and the effects on proliferation (CyQUANT®), apoptosis (SensoLyte® Homogeneous AMC Caspase- 3/7 Assay kit, western blotting), STAT3 DNA binding (EMSA), and vascular endothelial growth factor (VEGF), survivin, and matrix metalloproteinase-2 (MMP2) expression (RT-PCR, western blotting) were measured. STAT3 expression was measured by RT-PCR, qRT- PCR, and western blotting.Our data showed that FLLL32 decreased STAT3 DNA binding by EMSA. FLLL32 promoted loss of cell proliferation at lower concentrations than curcumin leading to caspase-3- dependent apoptosis, as evidenced by PARP cleavage and increased caspase 3/7 activity; this could be inhibited by treatment with the pan-caspase inhibitor Z-VAD-FMK. Treatment of OSA cells with FLLL32 decreased expression of survivin, VEGF, and MMP2 at both mRNA and protein levels with concurrent decreases in phosphorylated and total STAT3; this loss of total STAT3 occurred, in part, via the ubiquitin-proteasome pathway.These data demonstrate that the novel curcumin analog FLLL32 has biologic activity against OSA cell lines through inhibition of STAT3 function and expression. Future work with FLLL32 will define the therapeutic potential of this compound in vivo.', 'http://www.ncbi.nlm.nih.gov/pubmed/21443800', 'no', 'no', 'curcumin|FLLL32', 6),
(21453059, 'Wang W, Wang J, Song H, Liu J, Song B, Cao X', 'Cytotoxic T-lymphocyte antigen-4 +49G/A polymorphism is associated with increased risk of osteosarcoma.', 'Genet Test Mol Biomarkers', 'NA', 'Cytotoxic T-lymphocyte antigen-4 +49G/A polymorphism is associated with increased risk of osteosarcoma. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses anti-tumor response by down-regulating T-cell activation. CTLA-4 gene +49G/A polymorphism (rs231775) has been reported to be associated with various cancers. Objective: The objective of this study is to investigate the association between CTLA-4 gene +49G/A polymorphism and the susceptibility to osteosarcoma in the Chinese population.The CTLA-4 variant +49G/A was detected by polymerase chain reaction-restriction fragment length polymorphism in 205 osteosarcoma cases and 216 age-matched healthy controls. Data were analyzed using the Chi-square test.Frequencies of the CTLA-4 +49AA genotype and the +49A allele were significantly increased in patients with osteosarcoma compared to healthy controls (OR 2.27, p=0.010, and OR 1.41, p=0.015).Our data suggest that the +49G/A polymorphism of CTLA-4 gene is associated with increased susceptibility to osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21453059', 'yes', 'yes', 'NA', 1),
(21458381, 'Lockwood WW, Stack D, Morris T, Grehan D, O''Keane C, Stewart GL, Cumiskey J, Lam WL, Squire JA, Thomas DM, O''Sullivan MJ', 'Cyclin E1 is amplified and overexpressed in osteosarcoma.', 'J Mol Diagn', '2011', 'Cyclin E1 is amplified and overexpressed in osteosarcoma. Osteosarcoma is a genetically complex malignancy, predominantly afflicting the adolescent population and associated still with relatively poor long-term outcomes. Although there has been some improvement in the understanding of osteosarcoma biology, this has not yet translated particularly well into therapeutic advances. By using a whole-genome tiling path array for comparative genomic hybridization analysis, we sought to evaluate DNA copy number changes in 22 osteosarcoma tumor samples. Regions of most frequent gains or losses generated by Genomic Identification of Significant Targets in Cancer analysis were evaluated for genes of interest. Correlation of the copy number data with preexisting expression data for these genes yielded not only targets known to be important in osteosarcoma but also novel targets, notably cyclin E1. Fluorescence in situ hybridization and immunohistochemical analysis confirmed the findings. Overexpression of cyclin E1 has potential prognostic and therapeutic implications that are discussed herein.Copyright © 2011 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21458381', 'yes', 'yes', 'NA', 1),
(21460855, 'Su Y, Wagner ER, Luo Q, Huang J, Chen L, He BC, Zuo GW, Shi Q, Zhang BQ, Zhu G, Bi Y, Luo J, Luo X, Kim SH, Shen J, Rastegar F, Huang E, Gao Y, Gao JL, Yang K, Wietholt C, Li M, Qin J, Haydon RC, He TC, Luu HH', 'Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma.', 'Oncogene', '2011', 'Insulin-like growth factor binding protein 5 suppresses tumor growth and metastasis of human osteosarcoma. Osteosarcoma (OS) is the most common primary malignancy of bone. There is a critical need to identify the events that lead to the poorly understood mechanism of OS development and metastasis. The goal of this investigation is to identify and characterize a novel marker of OS progression. We have established and characterized a highly metastatic OS subline that is derived from the less metastatic human MG63 line through serial passages in nude mice via intratibial injections. Microarray analysis of the parental MG63, the highly metastatic MG63.2 subline, as well as the corresponding primary tumors and pulmonary metastases revealed insulin-like growth factor binding protein 5 (IGFBP5) to be one of the significantly downregulated genes in the metastatic subline. Confirmatory quantitative RT-PCR on 20 genes of interest demonstrated IGFBP5 to be the most differentially expressed and was therefore chosen to be one of the genes for further investigation. Adenoviral mediated overexpression and knockdown of IGFBP5 in the MG63 and MG63.2 cell lines, as well as other OS lines (143B and MNNG/HOS) that are independent of our MG63 lines, were employed to examine the role of IGFBP5. We found that overexpression of IGFBP5 inhibited in vitro cell proliferation, migration and invasion of OS cells. Additionally, IGFBP5 overexpression promoted apoptosis and cell cycle arrest in the G1 phase. In an orthotopic xenograft animal model, overexpression of IGFBP5 inhibited OS tumor growth and pulmonary metastases. Conversely, siRNA-mediated knockdown of IGFBP5 promoted OS tumor growth and pulmonary metastases in vivo. Immunohistochemical staining of patient-matched primary and metastatic OS samples demonstrated decreased IGFBP5 expression in the metastases. These results suggest 1) a role for IGFBP5 as a novel marker that has an important role in the pathogenesis of OS, and 2) that the loss of IGFBP5 function may contribute to more metastatic phenotypes in OS.', 'http://www.ncbi.nlm.nih.gov/pubmed/21460855', 'yes', 'no', 'NA', 1),
(21481226, 'Fossey SL, Bear MD, Kisseberth WC, Pennell M, London CA', 'Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines.', 'BMC Cancer', '2011', 'Oncostatin M promotes STAT3 activation, VEGF production, and invasion in osteosarcoma cell lines. We have previously demonstrated that both canine and human OSA cell lines, as well as 8 fresh canine OSA tumor samples, exhibit constitutive phosphorylation of STAT3, and that this correlates with enhanced expression of matrix metalloproteinase-2 (MMP2). While multiple signal transduction pathways can result in phosphorylation of STAT3, stimulation of the cytokine receptor gp130 through either IL-6 or Oncostatin M (OSM) is the most common mechanism through which STAT3 is activated. The purpose of this study was to evaluate the role of IL-6 and OSM stimulation on both canine and human OSA cell lines to begin to determine the role of these cytokines in the biology of OSA.RT-PCR and Western blotting were used to interrogate the consequences of OSM and IL-6 stimulation of OSA cell lines. OSA cells were stimulated with OSM and/or hepatocyte growth factor (HGF) and the effects on MMP2 activity (gel zymography), proliferation (CyQUANT), invasion (Matrigel transwell assay), and VEGF production (Western blotting, ELISA) were assessed. The small molecule STAT3 inhibitor LLL3 was used to investigate the impact of STAT3 inhibition following OSM stimulation of OSA cells.Our data demonstrate that the OSM receptor (OSMR), but not IL-6 or its receptor, is expressed by all human and canine OSA cell lines and canine OSA tumor samples; additionally, OSM expression was noted in all tumor samples. Treatment of OSA cell lines with OSM induced phosphorylation of STAT3, Src, and JAK2. OSM stimulation also resulted in a dose dependent increase in MMP2 activity and VEGF expression that was markedly reduced following treatment with the small molecule STAT3 inhibitor LLL3. Lastly, OSM stimulation of OSA cell lines enhanced invasion through Matrigel, particularly in the presence of rhHGF. In contrast, both OSM and HGF stimulation of OSA cell lines did not alter their proliferative capacity.These data indicate OSM stimulation of human and canine OSA cells induces STAT3 activation, thereby enhancing the expression/activation of MMP2 and VEGF, ultimately promoting invasive behavior and tumor angiogenesis. As such, OSM and its receptor may represent a novel target for therapeutic intervention in OSA.', 'http://www.ncbi.nlm.nih.gov/pubmed/21481226', 'no', 'no', 'NA', 3),
(21490307, 'Fu W, Ma L, Chu B, Wang X, Bui MM, Gemmer J, Altiok S, Pledger WJ', 'The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells.', 'Mol Cancer Ther', '2011', 'The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Although rare, osteosarcoma is an aggressive cancer that often metastasizes to the lungs. Toward the goal of developing new treatment options for osteosarcoma, we show that the cyclin-dependent kinase (CDK) inhibitor SCH 727965 (SCH) induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Cell lines prepared in our laboratory from patients who had received adjuvant chemotherapy and explants derived from a human osteosarcoma xenograft in mice were also responsive to SCH. Apoptosis occurred at low nanomolar concentrations of SCH, as did CDK inhibition, and was p53-independent. SCH activated the mitochondrial pathway of apoptosis as evidenced by caspase-9 cleavage and accumulation of cytoplasmic cytochrome c. Amounts of the apoptotic proteins Bax and Bim increased in mitochondria, whereas amounts of the antiapoptotic proteins Mcl-1 and Bcl-x(L) declined. Osteosarcoma cells apoptosed when codepleted of CDK1 and CDK2 but not when depleted of other CDK combinations. We suggest that SCH triggers the apoptosis of osteosarcoma cells by inactivating CDK1 and CDK2 and that SCH may be useful for treatment of drug-resistant osteosarcomas. SCH also induced the apoptosis of other sarcoma types but not of normal quiescent osteoblasts or fibroblasts.', 'http://www.ncbi.nlm.nih.gov/pubmed/21490307', 'no', 'no', 'dinacliclib', 8),
(21495021, 'Yang J, Yang D, Sun Y, Sun B, Wang G, Trent JC, Araujo DM, Chen K, Zhang W', 'Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma.', 'Cancer', '2011', 'Genetic amplification of the vascular endothelial growth factor (VEGF) pathway genes, including VEGFA, in human osteosarcoma. Osteosarcoma is the most common primary tumor of bone. It is a highly vascular and extremely destructive malignancy that mainly affects children and young adults. The authors conducted microarray-based comparative genomic hybridization (aCGH) and pathway analyses to gain a systemic view of pathway alterations in the genetically altered genes.Recurrent amplified and deleted genes that were detected by aCGH were subjected to an analysis based on the Kyoto Encyclopedia of Genes and Genomes to identify the altered pathways. Among the enriched pathways, vascular endothelial growth factor (VEGF) pathway genes collectively were amplified, and alterations of this pathway were validated by fluorescence in situ hybridization (FISH) and immunohistochemistry analyses in 58 formalin-fixed, paraffin-embedded osteosarcoma archival tissues that had clinical follow-up information.The pathway enrichment analyses of the aCGH data revealed that VEGF pathway genes, including the VEGFA gene itself, were amplified significantly in osteosarcoma. Genetic amplification of the VEGFA gene, both focally and in larger fragment, was validated by FISH analysis. It is noteworthy that amplification of the VEGFA gene and elevated expression of the VEGFA protein were associated significantly with microvascular density and adverse tumor-free survival in patients with osteosarcoma.The authors report for the first time that VEGF pathway genes, including the VEGFA gene, are amplified in osteosarcoma. Amplification of the VEGFA gene is not only an important mechanism for elevated VEGFA protein expression but also is a poor prognostic factor for tumor-free survival. Combined classification of VEGFA gene amplification and positive VEGFA protein expression may provide a more accurate stratification method of selecting anti-VEGF therapy for patients with osteosarcoma.Copyright © 2011 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21495021', 'yes', 'yes', 'NA', 1),
(21506130, 'Nagao H, Ijiri K, Hirotsu M, Ishidou Y, Yamamoto T, Nagano S, Takizawa T, Nakashima K, Komiya S, Setoguchi T', 'Role of GLI2 in the growth of human osteosarcoma.', 'J Pathol', '2011', 'Role of GLI2 in the growth of human osteosarcoma. The Hedgehog pathway functions as an organizer in embryonic development. Aberrant activation of the Hedgehog pathway has been reported in various types of malignant tumours. The GLI2 transcription factor is a key mediator of Hedgehog pathway but its contribution to neoplasia is poorly understood. To establish the role of GLI2 in osteosarcoma, we examined its expression by real-time PCR using biopsy tissues. To examine the function of GLI2, we evaluated the growth of osteosarcoma cells and their cell cycle after GLI2 knockdown. To study the effect of GLI2 activation, we examined mesenchymal stem cell growth and the cell cycle after forced expression of GLI2. We found that GLI2 was aberrantly over-expressed in human osteosarcoma biopsy specimens. GLI2 knockdown by RNA interferences prevented osteosarcoma growth and anchorage-independent growth. Knockdown of GLI2 promoted the arrest of osteosarcoma cells in G(1) phase and was accompanied by reduced protein expression of the cell cycle accelerators cyclin D1, SKP2 and phosphorylated Rb. On the other hand, knockdown of GLI2 increased the expression of p21(cip1) . In addition, over-expression of GLI2 promoted mesenchymal stem cell proliferation and accelerated their cell cycle progression. Finally, evaluation of mouse xenograft models showed that GLI2 knockdown inhibited the growth of osteosarcoma in nude mice. Our findings suggest that inhibition of GLI2 may represent an effective therapeutic approach for patients with osteosarcoma.Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.', 'http://www.ncbi.nlm.nih.gov/pubmed/21506130', 'yes', 'yes', 'NA', 5),
(21508379, 'Uejima D, Nishijo K, Kajita Y, Ishibe T, Aoyama T, Kageyama S, Iwaki H, Nakamura T, Iida H, Yoshiki T, Toguchida J', 'Involvement of cancer biomarker C7orf24 in the growth of human osteosarcoma.', 'Anticancer Res', '2011', 'Involvement of cancer biomarker C7orf24 in the growth of human osteosarcoma. Up-regulation of the expression of the gene C7orf24, encoding γ-glutamyl cyclotransferase, is a common event in cancers derived from various tissues, but its involvement in osteosarcomas (OS) has not yet been demonstrated.The expression of C7orf24 was analyzed in human OS cell lines and primary tumor samples. The biological effects of C7orf24 on growth, motility, and invasion in the OS cell lines were investigated using siRNA for C7orf24. Genes related to the function of C7orf24 were sought by genome-wide gene expression profiling.The level of C7orf24 expression was much higher in the OS cell lines and OS primary tumors than in normal osteoblasts. Down-regulation of C7orf24 expression inhibited the growth of the cell lines in association with enhancement of cell-clustering. Treatment with C7orf24-siRNA inhibited cell motility and invasion. Gene ontology suggested the function of C7orf24 to be related to cell adhesion and protein transport.C7orf24 is also involved in the growth of OS, and is a potential biomarker for this type of tumor.', 'http://www.ncbi.nlm.nih.gov/pubmed/21508379', 'yes', 'no', 'NA', 1);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(21517265, 'Zhang F, Chen A, Chen J, Yu T, Guo F', 'SiRNA-mediated silencing of beta-catenin suppresses invasion and chemosensitivity to doxorubicin in MG-63 osteosarcoma cells.', 'Asian Pac J Cancer Prev', '2011', 'SiRNA-mediated silencing of beta-catenin suppresses invasion and chemosensitivity to doxorubicin in MG-63 osteosarcoma cells. beta-catenin, the chief oncogenic component of the canonical Wnt pathway, is known to be involved in development of a variety of cancers, but its role in human osteosarcomas is not fully understood. Here we investigate the effect of small interfering RNA-mediated beta-catenin knockdown on the survival, invasion and chemosensitivity of a human osteosarcoma cell line.A siRNA against beta-catenin was constructed and transfected into MG-63 cells. Expression of beta-catenin was determined by qRT-PCR and Western blotting. Cell growth and apoptosis were assessed in the presence or absence of doxorubicin by MTT and flow cytometry, respectively, cell invasion by transwell assay, and XIAP, Bclxl, nulear P65 and MT1-MMP expression by western blot and real-time PCR.Transfection of beta-catenin siRNA resulted in decreased expression of beta-catenin, suppression of invasion and motility of MG-63 cells and reduced chemosensitivity to doxorubicin in vitro, but little change in cell growth and apoptosis. At the same time, down-regulation of MT1-MMP and up-regulation of NF-kappaB activation were observed.Knock-down of beta-catenin gene may decrease the invasion ability through down-regulation of MT1-MMP expression and enhance the chemoresistance to doxorubicin via the NF-kappaB pathway. In contrast to other tumors, beta-catenin may not play an oncogenic role in osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21517265', 'no', 'no', 'doxorubicin', 3),
(21520041, 'Micutkova L, Hermann M, Offterdinger M, Hess MW, Matscheski A, Pircher H, Mück C, Ebner HL, Laich A, Ferrando-May E, Zwerschke W, Huber LA, Jansen-Dürr P', 'Analysis of the cellular uptake and nuclear delivery of insulin-like growth factor binding protein-3 in human osteosarcoma cells.', 'Int J Cancer', '2012', 'Analysis of the cellular uptake and nuclear delivery of insulin-like growth factor binding protein-3 in human osteosarcoma cells. Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) regulates cell proliferation and survival by extracellular interaction and inactivation of the growth factor IGF-I. Beyond that, IGF-independent actions mediated by intracellular IGFBP-3 including nuclear-IGFBP-3, have also been described. We here show, using both confocal and electron microscopy and cell fractionation, that the extracellular addition of IGFBP-3 to living cells results in rapid uptake and nuclear delivery of IGFBP-3, by yet partly unknown mechanisms. IGFBP-3 is internalized through a dynamin-dependent pathway, traffics through endocytic compartments and is finally delivered into the nucleus. We observed docking of IGFBP-3 containing structures to the nuclear envelope and found IGFBP-3 containing dot-like structures to permeate the nuclear envelope. In summary, our findings establish the pathway by which this tumor suppressor protein is delivered from extracellular space to the nucleus.Copyright © 2011 UICC.', 'http://www.ncbi.nlm.nih.gov/pubmed/21520041', 'no', 'no', 'NA', 2),
(21527497, 'Gross KL, Oakley RH, Scoltock AB, Jewell CM, Cidlowski JA', 'Glucocorticoid receptor alpha isoform-selective regulation of antiapoptotic genes in osteosarcoma cells: a new mechanism for glucocorticoid resistance.', 'Mol Endocrinol', '2011', 'Glucocorticoid receptor alpha isoform-selective regulation of antiapoptotic genes in osteosarcoma cells: a new mechanism for glucocorticoid resistance. Glucocorticoids regulate a variety of physiological processes and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR)α isoform. Recent data suggest that the mature GRα mRNA is translated into multiple N-terminal isoforms that have distinct biochemical properties and gene regulatory profiles. Interestingly, osteosarcoma cells stably expressing the GRα-D translational isoform are unique in that they are resistant to glucocorticoid-induced apoptosis. In this study, we investigate whether GRα isoform-specific differences in the regulation of antiapoptotic genes contribute to this resistant phenotype. We now show that GRα-D, unlike the other receptor isoforms, does not inhibit the activity of a nuclear factor κB (NF-κB)-responsive reporter gene and does not efficiently repress either the transcription or protein production of the antiapoptotic genes Bcl-xL, cellular inhibitor of apoptosis protein 1, and survivin. The inability of GRα-D to down-regulate the expression of these genes appears to be associated with a diminished interaction between GRα-D and NF-κB that is observed in cells, but not in vitro, and likely reflects the sequestration of GRα-D in the nucleus. Deletion of the GRα N-terminal amino acids 98-335 also results in a nuclear resident GR, which fails to interact with NF-κB in cells and promote apoptosis in response to glucocorticoids. These data suggest that the N-terminal translational isoforms of GRα selectively regulate antiapoptotic genes and that the GRα-D isoform may contribute to the resistance of certain cancer cells to glucocorticoid-induced apoptosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21527497', 'no', 'no', 'NA', 5),
(21528673, 'Boss DS, Glen H, Beijnen JH, de Jong D, Wanders J, Evans TR, Schellens JH', 'Serum beta-HCG and CA-125 as tumor markers in a patient with osteosarcoma: case report.', 'Tumori', 'NA', 'Serum beta-HCG and CA-125 as tumor markers in a patient with osteosarcoma: case report. Elevated beta-HCG serum levels are usually an indication of pregnancy or pregnancy-related disorders, but beta-HCG can also be elevated in testis and germ cell tumors. HCG expression by osteosarcoma is a rare phenomenon, with a few documented cases. CA-125 is commonly used to monitor disease progression and treatment response in ovarian cancer. CA-125 expression in patients with osteosarcoma has not previously been documented.Elevated beta-HCG and CA-125 serum levels were observed in a female patient of 57 years of age with metastatic osteosarcoma during screening investigations prior to participation in a phase I clinical trial. Pregnancy was excluded. Immunohistochemical studies revealed the tumor to be the source of the elevated beta-HCG serum levels. We found no CA-125 expression in tumor tissue. The patient was treated with E7080, a novel oral multi-targeted tyrosine kinase inhibitor. We measured serum beta-HCG and CA-125 to monitor treatment response. She had a significant clinical and radiological response after two cycles of treatment, but developed progressive disease after the third cycle. The beta-HCG serum levels seemed to better reflect her disease status than those of the other tumor marker, CA-125.When elevated, beta-HCG serum levels in patients with osteosarcoma might be used to monitor treatment. Treatment of advanced osteosarcoma with tyrosine kinase inhibitors, including E7080, warrants further investigation.', 'http://www.ncbi.nlm.nih.gov/pubmed/21528673', 'yes', 'no', 'E7080', 1),
(21529352, 'PosthumaDeBoer J, Würdinger T, Graat HC, van Beusechem VW, Helder MN, van Royen BJ, Kaspers GJ', 'WEE1 inhibition sensitizes osteosarcoma to radiotherapy.', 'BMC Cancer', '2011', 'WEE1 inhibition sensitizes osteosarcoma to radiotherapy. The use of radiotherapy in osteosarcoma (OS) is controversial due to its radioresistance. OS patients currently treated with radiotherapy generally are inoperable, have painful skeletal metastases, refuse surgery or have undergone an intralesional resection of the primary tumor. After irradiation-induced DNA damage, OS cells sustain a prolonged G(2) cell cycle checkpoint arrest allowing DNA repair and evasion of cell death. Inhibition of WEE1 kinase leads to abrogation of the G(2) arrest and could sensitize OS cells to irradiation induced cell death.WEE1 expression in OS was investigated by gene-expression data analysis and immunohistochemistry of tumor samples. WEE1 expression in OS cell lines and human osteoblasts was investigated by Western blot. The effect of WEE1 inhibition on the radiosensitivity of OS cells was assessed by cell viability and caspase activation analyses after combination treatment. The presence of DNA damage was visualized using immunofluorescence microscopy. Cell cycle effects were investigated by flow cytometry and WEE1 kinase regulation was analyzed by Western blot.WEE1 expression is found in the majority of tested OS tissue samples. Small molecule drug PD0166285 inhibits WEE1 kinase activity. In the presence of WEE1-inhibitor, irradiated cells fail to repair their damaged DNA, and show higher levels of caspase activation. The inhibition of WEE1 effectively abrogates the irradiation-induced G(2) arrest in OS cells, forcing the cells into premature, catastrophic mitosis, thus enhancing cell death after irradiation treatment.We show that PD0166285, a small molecule WEE1 kinase inhibitor, can abrogate the G(2) checkpoint in OS cells, pushing them into mitotic catastrophe and thus sensitizing OS cells to irradiation-induced cell death. This suggests that WEE1 inhibition may be a promising strategy to enhance the radiotherapy effect in patients with OS.', 'http://www.ncbi.nlm.nih.gov/pubmed/21529352', 'yes', 'yes', 'PD0166285', 1),
(21542455, 'Wang T, Hao L, Feng Y, Wang G, Qin D, Gu G', 'Knockdown of MED19 by lentivirus-mediated shRNA in human osteosarcoma cells inhibits cell proliferation by inducing cell cycle arrest in the G0/G1 phase.', 'Oncol Res', '2011', 'Knockdown of MED19 by lentivirus-mediated shRNA in human osteosarcoma cells inhibits cell proliferation by inducing cell cycle arrest in the G0/G1 phase. MED 19 is a subunit of the mediator complex, which is a coactivator of RNA polymerase II and also interacts with the downstream coding region of many genes. However, the role of MED19 in osteosarcoma is unknown. In the present study, we applied lentivirus-mediated short hairpin RNA (shRNA)-triggered RNA interference to downregulate MED19 expression in human osteosarcoma SaOS-2 and U2OS cells. Knockdown of MED19 expression was confirmed by real-time PCR and Western blot. It was found that silencing of MED19 resulted in decreased cell viability, colony formation capacity, and DNA synthesis ability in both cells, as well as the G0/G1 phase cell cycle arrest. These results implied that MED19 played an important role in cell growth and cell cycle progression of human osteosarcoma cells. MED19 may be an attractive candidate for the therapeutic target in osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21542455', 'no', 'no', 'NA', 1),
(21563968, 'Wang W, Song H, Liu J, Song B, Cao X', 'CD86 + 1057G/A polymorphism and susceptibility to osteosarcoma.', 'DNA Cell Biol', '2011', 'CD86 + 1057G/A polymorphism and susceptibility to osteosarcoma. CD86 (B7-2), one of the costimulatory molecules on antigen-presenting cells, plays essential roles not only in autoimmunity and transplantation but also in tumor immunity. CD86 + 1057G/A polymorphism (rs1129055) is associated with various diseases. The objective of this study was to investigate the association between CD86  + 1057G/A polymorphism and susceptibility to osteosarcoma in a Chinese population. The CD86 + 1057G/A mutation was detected by polymerase chain reaction-restriction fragment length polymorphism in 205 osteosarcoma cases and 216 age-matched healthy controls. Frequencies of CD86 + 1057 AA genotype and +1057 A allele were significantly increased in osteosarcoma patients than in healthy controls (odds ratio = 2.18, 95% confidence interval, 1.21-3.93, p = 0.008; and odds ratio = 1.43, 95% confidence interval, 1.08-1.88, p = 0.011). Our data suggest that the +1057G/A polymorphism of the CD86 gene is associated with increased susceptibility to osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21563968', 'yes', 'yes', 'NA', 1),
(21573491, 'Lin CC, Kuo CL, Lee MH, Lai KC, Lin JP, Yang JS, Yu CS, Lu CC, Chiang JH, Chueh FS, Chung JG', 'Wogonin triggers apoptosis in human osteosarcoma U-2 OS cells through the endoplasmic reticulum stress, mitochondrial dysfunction and caspase-3-dependent signaling pathways.', 'Int J Oncol', '2011', 'Wogonin triggers apoptosis in human osteosarcoma U-2 OS cells through the endoplasmic reticulum stress, mitochondrial dysfunction and caspase-3-dependent signaling pathways. Wogonin (5,7-dihydroxy-8-methoxyflavone) is a flavone constituent of Scutellaria baicalensis with various beneficial biological activities and it has been shown to have tumor therapeutic potential in vitro and in vivo. The purpose of this study was to investigate the effects of wogonin in a human osteosarcoma cell line (U-2 OS). Results showed that a dose- and time-dependent reduction occurred in cell viability after exposure to wogonin in U-2 OS cells. Increasing the levels of reactive oxygen species (ROS) and Ca2+ but decreasing the levels of mitochondrial membrane potential (∆Ψm) were examined in wogonin-treated U-2 OS cells. Flow cytometric assay indicated that wogonin induced sub-G1 phase (apoptosis) and increased caspase-3 activity in examined cells. Wogonin-induced apoptosis in U-2 OS cells was also confirmed by 4'',6-diamidino-2-phenylindole (DAPI) staining. Also, results from Western blotting indicated that wogonin increased the levels of Bad, Bax, cytochrome c, cleaved caspase-9, cleaved caspase-3, AIF, Endo G, Fas/CD95, caspase-8, GADD153, GRP78, ATF-6α, calpain 1, calpain 2 and caspase-4 then leading to cell apoptosis. In conclusion, wogonin induced ROS production and intracellular Ca2+, and altered the levels of anti- (Bcl-2) and pro- (Bad and Bax) apoptotic proteins. Wogonin-induced apoptosis in U-2 OS cells was through the activation of caspase-3. In conclusion, these are the first findings to show wogonin-induced cytotoxic effects through induction of apoptotic cell death and ER stress in U-2 OS cells. The potent in vitro antitumor activities suggest that wogonin could be developed for the treatment of human osteosarcoma in the future.', 'http://www.ncbi.nlm.nih.gov/pubmed/21573491', 'no', 'no', 'wogonin', 16),
(21573994, 'Yuan S, Pan Q, Fu C, Bi Z', 'Silencing of HMGA1 expression by RNA interference suppresses growth of osteogenic sarcoma.', 'Mol Cell Biochem', '2011', 'Silencing of HMGA1 expression by RNA interference suppresses growth of osteogenic sarcoma. The expression of high mobility group protein A1 (HMGA1) protein has been closely related to various malignant and prognostic degrees of tumor. To investigate the influence of down-regulating HMGA1 on the tumor and the mechanism underlying antitumor of HMGA1, we transfected the HMGA1 shRNA vector into the osteogenic sarcoma MG-63 cell and observed the changes of cell proliferation, invasion abilities, and the tumor growth. HMGA1 gene expression could be efficiently inhibited, and cell proliferation, migration, invasion, and matrix metalloprotease level were also decreased. BALB/C nude mice injected with the MG-63 cells transfected HMGA1 shRNA showed the significant lower tumor weight, tumor volume, and longer tumor-forming time compared with the control group. Our results suggest that knockdown of HMGA1 could inhibit growth and metastasis potentials of MG-63 cells, which may be a therapeutic target protein for osteogenic sarcoma and may be of biological importance.', 'http://www.ncbi.nlm.nih.gov/pubmed/21573994', 'no', 'no', 'NA', 1),
(21617855, 'Miwa S, Sugimoto N, Shirai T, Hayashi K, Nishida H, Ohnari I, Takeuchi A, Yachie A, Tsuchiya H', 'Caffeine activates tumor suppressor PTEN in sarcoma cells.', 'Int J Oncol', '2011', 'Caffeine activates tumor suppressor PTEN in sarcoma cells. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Akt activation exerts a strong anti-apoptotic effect and inhibits key pro-apoptotic proteins. We investigated the effect of caffeine in the prevention of tumor cell proliferation and induction of cell death. We found that caffeine induced increased intracellular cAMP levels, PTEN activation and Akt inactivation, which together prevented proliferation of human osteosarcoma cells (MG63) and fibrosarcoma cells (HT1080). PTEN knockdown by siRNA reduced the effects of caffeine on Akt inactivation in osteosarcoma cells. These results indicate that the tumor suppressor PTEN signaling pathway contributes to the growth-inhibitory effect of caffeine on sarcoma cells. Our data suggest that caffeine and other drugs that act on this pathway could have promising therapeutic effects in the treatment of sarcoma patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/21617855', 'no', 'no', 'caffeine', 2),
(21617882, 'Xie X, Yin J, Jia Q, Wang J, Zou C, Brewer KJ, Colombo C, Wang Y, Huang G, Shen J', 'Quercetin induces apoptosis in the methotrexate-resistant osteosarcoma cell line U2-OS/MTX300 via mitochondrial dysfunction and dephosphorylation of Akt.', 'Oncol Rep', '2011', 'Quercetin induces apoptosis in the methotrexate-resistant osteosarcoma cell line U2-OS/MTX300 via mitochondrial dysfunction and dephosphorylation of Akt. Quercetin is the most abundant polyphenolic flavonoid found in plants. Several studies suggest that it has potent anticancer effects. The present study examines the apoptosis-inducing activity and the underlying mechanism of action of quercetin in a methotrexate (MTX)-resistant osteosarcoma model. Our results showed that quercetin inhibited cell viability in a dose-dependent manner and there was no cross-resistance between MTX and quercetin in U2-OS/MTX300 cells. The induction of apoptosis was observed by flow cyto-metry and fluorescence staining experiments. Quercetin-induced apoptosis was accompanied by a significant reduction of mitochondrial membrane potential, release of mitochondrial cytochrome c to the cytosol, activation of caspase-3, down-regulation of Bcl-2, p-Bad and up-regulation of Bax. A remarkable dephospho-rylation of Akt was also detected after quercetin treatment. Furthermore, transduction with constitutively active Akt protected against the quercetin-induced dephosphorylation of Akt and Bad as well as poly(ADP-ribose)polymerase (PARP) degradation, while combined treatment with quercetin and LY294002 enhanced the dephosphorylation of Akt, Bad and PARP cleavage in U2-OS/MTX300 cells. Taken together, our results demonstrate that quercetin-induced apoptosis in the MTX-resistant osteosarcoma cells U2-OS/MTX300 was mediated via mitochondrial dysfunction and dephosphorylation of Akt.', 'http://www.ncbi.nlm.nih.gov/pubmed/21617882', 'no', 'no', 'quercetin', 6),
(21619552, 'Cui Q, Li D, Liu C, Guo J, Liu S, Liu Y, Wang X, Zeng Y', 'The significance of MGMT protein detection in evaluation of osteosarcoma necrosis rate after cisplatin chemotherapy.', 'Bosn J Basic Med Sci', '2011', 'The significance of MGMT protein detection in evaluation of osteosarcoma necrosis rate after cisplatin chemotherapy. The aim of this article was to investigate the correlation between expression of O(6)-methylguanine-DNA methyltransferase (MGMT) in osteosarcoma and the curative effect of alkylating agent (Cis-diaminodichloroplatinum, CDDP). 42 male patients and 34 female patients with a median age of 17 years (9 to 43 years) were eligible for this study. According to histopathological types, there were 3 cases of telangiectatic osteogenic sarcoma, 22 cases of osteoblastic, 11 cases of chondroblastic and 16 cases of fibroblastic sarcoma. Immunohistochemical method was used to detect the expression of MGMT protein. The correlations between MGMT expression and the curative effect of CDDP on osteosarcoma have been investigated. It was shown by immunohistochemical staining that among 76 osteosarcoma biopsy specimens, 52 (68%) cases were positive, 27 (35%) cases were weak positive, 18 (24%), cases were moderate positive, and 7 (9%) cases were strong positive. There were no significant differences in MGMT expression among different pathological types of tumors (p>0.5). After CDDP chemotherapy, among pathologic specimens in which MGMT expression was positive, necrosis rates were as follows: grade I, 5 cases (38%); grade II, 7 cases (25%); grade III, 15 cases (21%); grade IV, 2 cases (23%). Osteosarcoma necrosis rate was low when the expression of MGMT protein was positive, whereas necrosis rate was high when there was a low level of MGMT expression (p<0.01). There was a significant negative correlation between the level of MGMT expression in osteosarcoma tissue and osteosarcoma necrosis rate after cisplatin chemotherapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/21619552', 'yes', 'no', 'Cis-diaminodIHCloroplatinum', 1),
(21619704, 'Mirabello L, Yu K, Berndt SI, Burdett L, Wang Z, Chowdhury S, Teshome K, Uzoka A, Hutchinson A, Grotmol T, Douglass C, Hayes RB, Hoover RN, Savage SA', 'A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma.', 'BMC Cancer', '2011', 'A comprehensive candidate gene approach identifies genetic variation associated with osteosarcoma. Osteosarcoma (OS) is a bone malignancy which occurs primarily in adolescents. Since it occurs during a period of rapid growth, genes important in bone formation and growth are plausible modifiers of risk. Genes involved in DNA repair and ribosomal function may contribute to OS pathogenesis, because they maintain the integrity of critical cellular processes. We evaluated these hypotheses in an OS association study of genes from growth/hormone, bone formation, DNA repair, and ribosomal pathways.We evaluated 4836 tag-SNPs across 255 candidate genes in 96 OS cases and 1426 controls. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI).Twelve SNPs in growth or DNA repair genes were significantly associated with OS after Bonferroni correction. Four SNPs in the DNA repair gene FANCM (ORs 1.9-2.0, P = 0.003-0.004) and 2 SNPs downstream of the growth hormone gene GH1 (OR 1.6, P = 0.002; OR 0.5, P = 0.0009) were significantly associated with OS. One SNP in the region of each of the following genes was significant: MDM2, MPG, FGF2, FGFR3, GNRH2, and IGF1.Our results suggest that several SNPs in biologically plausible pathways are associated with OS. Larger studies are required to confirm our findings.', 'http://www.ncbi.nlm.nih.gov/pubmed/21619704', 'yes', 'yes', 'NA', 8),
(21631272, 'de la Roza G', 'p63 expression in giant cell-containing lesions of bone and soft tissue.', 'Arch Pathol Lab Med', '2011', 'p63 expression in giant cell-containing lesions of bone and soft tissue. Previous studies have demonstrated p63 overexpression in giant cell tumors of bone and advocate its use as a potential diagnostic marker. Although routine histology is often all that is required to diagnose giant cell tumor of bone, immunohistochemistry could prove useful to distinguish it from other benign and malignant giant cell-containing lesions of bone and soft tissue on needle biopsies and unusual clinical settings.To assess p63 expression in giant cell-containing lesions of bone and soft tissue.p63 immunohistochemistry was performed in 23 giant cell tumors of bone, 8 primary aneurysmal bone cysts, 12 chondroblastomas, 4 giant cell reparative granulomas, 4 osteosarcomas, 15 tenosynovial giant cell tumors, 6 nonossifying fibromas, and 4 pigmented villonodular synovitides.p63 overexpression was identified in 20 of 23 giant cell tumors of bone (86.9%), 5 of 8 primary aneurysmal bone cysts (62.5%), 10 of 12 chondroblastomas (83.3%), 4 of 4 giant cell reparative granulomas (100%), 2 of 4 osteosarcomas (50%), 1 of 15 tenosynovial giant cell tumors (6.6%), 1 of 6 nonossifying fibromas (16.6%), and 1 of 4 pigmented villonodular synovitides (25%). The sensitivity, specificity, positive predictive value, and negative predictive value of p63 immunohistochemistry for the diagnosis of giant cell tumor of bone were 86.95%, 53.36%, 45.45%, and 91.17%, respectively.This study shows that although p63 is expressed by most giant cell tumors of bone, its lack of specificity limits its use as an immunohistochemical marker in the differential diagnosis of giant cell-containing lesions of bone and soft tissue.', 'http://www.ncbi.nlm.nih.gov/pubmed/21631272', 'yes', 'yes', 'NA', 1),
(21640141, 'Kimura R, Ishikawa C, Rokkaku T, Janknecht R, Mori N', 'Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells.', 'Biochim Biophys Acta', '2011', 'Phosphorylated c-Jun and Fra-1 induce matrix metalloproteinase-1 and thereby regulate invasion activity of 143B osteosarcoma cells. Osteosarcoma is the most common primary malignancy of bone and patients often develop pulmonary metastases. Despite the advances in surgical and medical management, the mechanisms underlying human osteosarcoma progression and metastasis remain to be elucidated. Gene expression profiles were compared by the cDNA microarray technique between two different human osteosarcoma sublines, MNNG/HOS and 143B, which differ greatly in spontaneous pulmonary metastatic potential. Here we report an enhanced expression of matrix metalloproteinase (MMP)-1 in the highly metastatic human osteosarcoma cell line 143B. Moreover, the in vitro invasion activity of 143B cells was MMP-1-dependent. The activator protein (AP)-1 binding site in the MMP-1 gene promoter was required for the constitutive expression of MMP-1 in 143B cells. Two AP-1 components, c-Jun and Fra-1, were phosphorylated, and bound to the AP-1 binding site of the MMP-1 promoter in 143B cells. Activated c-Jun and Fra-1 were essential for MMP-1 gene expression in 143B cells. Mitogen-activated protein kinase pathways including the c-Jun NH(2)-terminal kinase and the extracellular signal-regulated kinase activate c-Jun and Fra-1 and thereby regulate c-Jun/Fra-1 mediated events, establishing the mitogen-activated protein kinase/AP-1/MMP-1 axis as important in 143B cells. These data suggest that MMP-1 plays a central role in osteosarcoma invasion. Accordingly, MMP-1 might be a biomarker and therapeutic target for invasive osteosarcomas and pulmonary metastases.2011 Elsevier B.V. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21640141', 'no', 'no', 'NA', 3),
(21656314, 'Zhao Y, Liao Q, Zhu Y, Long H', 'Endothelin-1 promotes osteosarcoma cell invasion and survival against cisplatin-induced apoptosis.', 'Clin Orthop Relat Res', '2011', 'Endothelin-1 promotes osteosarcoma cell invasion and survival against cisplatin-induced apoptosis. Endothelin-1 (ET-1) participates in a wide range of cancer-relevant processes including cell proliferation, inhibition of apoptosis, matrix remodeling, bone deposition, and metastases. Although ET-1 reportedly promotes osteosarcoma (OS) cell invasion, suggesting an important role of ET-1 in OS metastasis, the role of ET-1 in OS remains unclear. QUESTION/PURPOSES: We asked whether (1) ET-1 expression is associated with the malignancy of OS, (2) ET-1 enhances the cell invasion ability of OS, and (3) ET-1 promotes OS cell survival against apoptotic stress.We cultured primary OS specimens from 22 patients with Stages II (OS-II) and III (OS-III) in real-time quantitative RT-PCR and ELISA to compare ET-1 expression. We used Transwell(®) cell invasion assays (in triplicate) to assess the invasion ability of cells in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We compared cell apoptosis rate among the cells treated with cisplatin in the presence or absence of exogenous ET-1 and/or ET receptor antagonists. We used OS cell line MG-63 in all experiments as a reference.Real-time quantitative RT-PCR and ELISA showed OS-III cells had greater ET-1 expression than OS-II cells at the mRNA and the secreted protein levels. Transwell(®) cell invasion assays showed OS-III cells had a greater migrated cell number than OS-II cells, which could be abrogated by ET(A) receptor antagonist BQ123 (100 pmol/L), but not ET(B) receptor antagonist BQ788 (1 μmol/L); exogenous ET-1 dose-dependently promoted OS cell migration, which could be inhibited by BQ123 (100 pmol/L). Cisplatin (10 nmol/L) induced less apoptosis in OS-III cells than in OS-II cells; exogenous ET-1 dose-dependently promoted OS cell survival against cisplatin-induced apoptosis; both effects were reversed by BQ123 (1 μmol/L), but not BQ788 (1 μmol/L).Increased ET-1 expression appears to be associated with increased malignancy of OS. ET-1 promotes OS cell invasion and survival against cisplatin-induced apoptosis through the ET(A) receptor.The ET-1/ET(A) pathway may represent an important target for treating OS, because blocking the ET(A) receptor with a selective antagonist can inhibit OS cell invasion and potentiate a chemotherapeutic agent''s effect on OS.', 'http://www.ncbi.nlm.nih.gov/pubmed/21656314', 'no', 'no', 'NA', 1),
(21665377, 'Yoshitani K, Kido A, Honoki K, Akahane M, Fujii H, Tanaka Y', 'Low concentrations of alendronate increase the local invasive potential of osteoblastic sarcoma cell lines via connexin 43 activation.', 'Pathol Res Pract', '2011', 'Low concentrations of alendronate increase the local invasive potential of osteoblastic sarcoma cell lines via connexin 43 activation. Bisphosphonates (BPs) are agents used for treating disorders of excessive bone resorption. In addition, due to their cell-killing activity, BPs were potent candidates for adjuvant cancer therapy. On the other hand, low-concentrations of BPs have been reported to increase cellular viability in several types of tumor cells. Therefore, we focused on the effect of BPs on cellular aggressiveness of malignant bone tumors at low concentrations. MTS assay was performed using osteosarcoma cell lines MG63 and HOS, fibrosarcoma cell line HT1080, and prostate cancer cell line PC3. All the cell lines showed toxicity at high concentrations. On the other hand, at lower concentrations, the cellular viabilities of HOS and MG63 were rather higher than those of untreated controls. Since this tendency was most evident, HOS was used for further assays, including cellular motility, bone resorption activity, and cathepsin K activity. The low-concentration of alendronate enhanced cellular viability and motility, which correlated with the expression of connexin 43 at the mRNA and protein levels. Interestingly, oleamide, a potent connexin 43 inhibitor, had an inhibitory effect on the enhanced proliferation. Our data suggest that alendronate may enhance the proliferation of osteoblastic cell line through connexin 43 activation.Copyright © 2011 Elsevier GmbH. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21665377', 'no', 'no', 'alendronate', 1),
(21666078, 'Duan Z, Choy E, Harmon D, Liu X, Susa M, Mankin H, Hornicek F', 'MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration.', 'Mol Cancer Ther', '2011', 'MicroRNA-199a-3p is downregulated in human osteosarcoma and regulates cell proliferation and migration. microRNAs (miRNA, miR) play an important role in cancer cell growth and migration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. By applying a miRNA microarray platform and unsupervised hierarchical clustering analysis, we found that several miRNAs have altered expression levels in osteosarcoma cell lines and tumor tissues when compared with normal human osteoblasts. Three miRNAs, miR-199a-3p, miR-127-3p, and miR-376c, were significantly decreased in osteosarcoma cell lines, whereas miR-151-3p and miR-191 were increased in osteosarcoma cell lines in comparison with osteoblasts. Transfection of precursor miR-199a-3p into osteosarcoma cell lines significantly decreased cell growth and migration, thus indicating that the inhibition effect is associated with an increase in the G(1)-phase and a decrease of the S-phase cell population. In addition, we observed decreased mTOR and Stat3 expression in miR-199a-3p transfected cells. This study provides new insights for miRNAs in osteosarcoma and suggests that miR-199a-3p may play a functional role in osteosarcoma cell growth and proliferation. Restoring miR-199a-3p''s function may provide therapeutic benefits in osteosarcoma.©2011 AACR', 'http://www.ncbi.nlm.nih.gov/pubmed/21666078', 'yes', 'no', 'NA', 3),
(21667022, 'Chen KT, Hour MJ, Tsai SC, Chung JG, Kuo SC, Lu CC, Chiu YJ, Chuang YH, Yang JS', 'The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor.', 'Int J Oncol', '2011', 'The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor. Our previous study demonstrated that 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) possesses potential anticancer activity and exhibits greater antitumor effect than the other quinazoline compounds in human osteogenic sarcoma U-2 OS cells via in vitro screening. In this study, we focused on investigating the anti-metastatic activity and the signaling pathways involved in LJJ-10 action in U-2 OS cells. The results from wound healing and Boyden chamber transwell assays indicated that LJJ-10 exhibited an inhibitory effect on the migration and invasion of U-2 OS cells. LJJ-10 also inhibited matrix metalloproteinase-2 (MMP-2) and MMP-9 enzyme activities and caused a concentration-dependent decrease in protein levels by gelatin zymography assay and Western blot analysis, respectively. Meanwhile, LJJ-10 suppressed MMP-2 and MMP-9 mRNA levels in a concentration-dependent fashion after 12-h exposure in U-2 OS cells. Computational modeling showed that LJJ-10 is bound into the IGF-1R via hydrophobic interactions with Leu975, Val983, Ala1001, Glu1050 and Met1052 with one hydrogen bond between 6-F and Met1052. LJJ-10 reduced the protein levels of p-JNK, p-p38, p-ERK, p-AKT and p-IGFR by Western blotting and these influences are concentration-dependent. Based on these observations, this study suggests that molecular targeting of the insulin-like growth factor-I receptor (IGF-1R) signaling leads to the suppression of downstream MAPK/AKT signaling and downregulation of MMP-2 and -9 RNA levels and protein levels in LJJ-10-treated U-2 OS cells. Therefore, the inhibition of metastasis in human osteosarcoma cells by treatment with this novel agent, LJJ-10 may be a useful chemotherapeutic approach.', 'http://www.ncbi.nlm.nih.gov/pubmed/21667022', 'no', 'no', '6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline', 8),
(21671176, 'Fan L, Wu Q, Xing X, Liu Y, Shao Z', 'Targeted silencing of heparanase gene by small interfering RNA inhibits invasiveness and metastasis of osteosarcoma cells.', 'J Huazhong Univ Sci Technolog Med Sci', '2011', 'Targeted silencing of heparanase gene by small interfering RNA inhibits invasiveness and metastasis of osteosarcoma cells. The effects of targeted silencing of heparanase gene by small interfering RNA (siRNA) on invasiveness and metastasis of osteosarcoma cells (MG63 cells) were investigated in the present study. Two complementary oligonucleotide strands were synthesized and inserted into pGenesil-1 vector based on the mRNA sequence of heparanase gene. The expression vector containing short hairpin RNA (pGenesil-shRNA) was constructed successfully. MG63 cells were randomly allocated into 3 groups: blank group, empty vector (pGenesil) transfected group and expression vector (pGenesil-shRNA) transfected group. Under the induction of Lipofectamine 2000, the recombinants were transfected into MG63 cells. Heparanase gene expression level was detected by RT-PCR and Western blotting. Cell proliferation was measured by MTT assay. Cell invasiveness and metastasis were examined by cell adhesion and Transwell-ECM assays. HUVECs migration assay was applied for the detection of angiogenesis. As compared with negative controls, the mRNA and protein expression levels of heparanase were down-regulated by 76.1% (P<0.01) and 75.3% (P<0.01) respectively in the pGenesil-shRNA transfected group. Meanwhile, the proliferation, adhesiveness, invasiveness and angiogenesis properties of MG63 cells were all significantly inhibited. It was suggested that targeted silencing of heparanase gene by siRNA could dramatically inhibit the invasiveness and metastasis of osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21671176', 'no', 'no', 'NA', 1),
(21671177, 'Zhang F, Chen A, Chen J, Yu T, Guo F', 'Influence of β-catenin small interfering RNA on human osteosarcoma cells.', 'J Huazhong Univ Sci Technolog Med Sci', '2011', 'Influence of β-catenin small interfering RNA on human osteosarcoma cells. This study examined the effect of small interfering RNA-mediated β-catenin knockdown on the survival, invasion and chemosensitivity of human osteosarcoma cells (U2-OS cells). The siRNA against β-catenin was constructed and transfected into U2-OS cells. The expression of β-catenin was detected by qRT-PCR and Western blotting. Cell growth and apoptosis was detected in the presence or absence of doxorubicin by MTT and flow cytometry, respectively. Cell invasion ability was measured by transwell assay. The results showed that the transfection of β-catenin siRNA resulted in decreased expression of β-catenin, suppression of invasion and motility of U2-OS cells, reduced chemosensitivity to doxorubicin in vitro, and little change in cell growth and apoptosis. Additionally, down-regulated MT1-MMP expression was found after transfection. It was concluded that knockdown of β-catenin gene may decrease the invasive ability of human osteosarcoma cells through down-regulated MT1-MMP expression, and the chemosensitivity of osteosarcoma cells against doxorubicin.', 'http://www.ncbi.nlm.nih.gov/pubmed/21671177', 'no', 'no', 'NA', 2),
(21681744, 'Marion A, Dieudonné FX, Patiño-Garcia A, Lecanda F, Marie PJ, Modrowski D', 'Calpain-6 is an endothelin-1 signaling dependent protective factor in chemoresistant osteosarcoma.', 'Int J Cancer', '2012', 'Calpain-6 is an endothelin-1 signaling dependent protective factor in chemoresistant osteosarcoma. Bone tumors strongly influence normal tissues and stimulate bone cells for the production of cytokines supporting proliferation and abnormal survival in cancer cells. We previously reported that the proteoglycan syndecan-2 controls the activity of various cytokines and growth factors and also modulates apoptosis and response to cytotoxic agents in osteosarcoma cell lines. Here, we show that syndecan-2 has a stronger tumor suppressor activity in vivo. We identify calpain-6 as a target gene downregulated by syndecan-2 in cells and in vivo. We demonstrate that calpain-6 expression in osteosarcoma cells depends on endothelin-1, a mediator of the tumor progression in bone. Syndecan-2 overexpression alters ERK1/2, PI3K/AKT and NFκB pathways that are calpain-6-promoting signals downstream of endothelin-1. Immunohistochemical analysis shows that calpain-6 is expressed in human bone tumors and metastases. A high expression of calpain-6 was specially found in recurrent osteosarcoma. Moreover, calpain-6 levels in primary tumors were inversely related to the response to chemotherapy. Consistently, calpain-6 was increased by doxorubicin and was found to be expressed at higher levels in doxorubicin-resistant U2OS osteosarcoma-derived cells as compared to responsive cells. Inhibition of calpain-6 with shRNA resulted in decreased proliferation, increased spontaneous apoptosis and increased sensitivity to doxorubicin and also methotrexate in responsive and resistant osteosarcoma cells. Taken together, our data show that syndecan-2 exerts its pro-apoptotic function through modulation of the endothelin-1/NFκB signaling and through downregulation of calpain-6, a protective factor that contributes to abnormal cell survival. Thus, this study identifies calpain-6 as a new possible therapeutic target in chemoresistant osteosarcoma.Copyright © 2011 UICC.', 'http://www.ncbi.nlm.nih.gov/pubmed/21681744', 'yes', 'no', 'methotrexate|doxorubicin', 2),
(21691740, 'Toledo SR, Zago MA, Oliveira ID, Proto-Siqueira R, Okamoto OK, Severino P, Vêncio RZ, Gamba FT, Silva WA, Moreira-Filho CA, Torre CA, Alves MT, Garcia-Filho RJ, Simpson AJ, Petrilli AS', 'Insights on PRAME and osteosarcoma by means of gene expression profiling.', 'J Orthop Sci', '2011', 'Insights on PRAME and osteosarcoma by means of gene expression profiling. Osteosarcoma (OS) is the most frequent bone tumor in children and adolescents. Tumor antigens are encoded by genes that are expressed in many types of solid tumors but are silent in normal tissues, with the exception of placenta and male germ-line cells. It has been proposed that antigen tumors are potential tumor markers.The premise of this study is that the identification of novel OS-associated transcripts will lead to a better understanding of the events involved in OS pathogenesis and biology.We analyzed the expression of a panel of seven tumor antigens in OS samples to identify possible tumor markers. After selecting the tumor antigen expressed in most samples of the panel, gene expression profiling was used to identify osteosarcoma-associated molecular alterations. A microarray was employed because of its ability to accurately produce comprehensive expression profiles.PRAME was identified as the tumor antigen expressed in most OS samples; it was detected in 68% of the cases. Microarray results showed differences in expression for genes functioning in cell signaling and adhesion as well as extracellular matrix-related genes, implying that such tumors could indeed differ in regard to distinct patterns of tumorigenesis.The hypothesis inferred in this study was gathered mostly from available data concerning other kinds of tumors. There is circumstantial evidence that PRAME expression might be related to distinct patterns of tumorigenesis. Further investigation is needed to validate the differential expression of genes belonging to tumorigenesis-related pathways in PRAME-positive and PRAME-negative tumors.', 'http://www.ncbi.nlm.nih.gov/pubmed/21691740', 'yes', 'no', 'NA', 1),
(21706236, 'Hua Y, Jia X, Sun M, Zheng L, Yin L, Zhang L, Cai Z', 'Plasma membrane proteomic analysis of human osteosarcoma and osteoblastic cells: revealing NDRG1 as a marker for osteosarcoma.', 'Tumour Biol', '2011', 'Plasma membrane proteomic analysis of human osteosarcoma and osteoblastic cells: revealing NDRG1 as a marker for osteosarcoma. Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. To identify new biomarkers for early diagnosis of OS and novel therapeutic candidates, we carried out a plasma membrane proteomic study based on two-dimensional electrophoresis (2DE). The OS cell line MG-63 and the human osteoblastic cell line hFOB1.19 were adopted as the comparison model. We extracted plasma membrane by aqueous two-phase partition extraction. The proteins were separated through 2DE. We analyzed the differentially expressed proteins by Imagemaster software and then identified them by liquid chromatography-tandem mass spectrometry, and the location and function of differential proteins were searched through the Gene Ontology database. In total, 220 protein spots were separated by 2DE. Seven proteins with more than 2.0-folds of difference were successfully identified from 13 gel spots, with 6 up-regulated and 1 down-regulated. Gene Ontology analysis of the differentially expressed proteins indicated that these proteins were involved in seven kinds of functions including binding, structural, cell motility, receptor activity, electron carrier activity, NADH dehydrogenase (ubiquinone) activity, and transcription repressor activity. The up-regulation of NDRG1 was verified in osteosarcoma through Western blotting and by immunohistochemistry in paraffin-embedded tissues. The plasma membrane proteins identified in this study may provide new insights into osteosarcoma cancer biology and potential diagnostic and therapeutic biomarkers.', 'http://www.ncbi.nlm.nih.gov/pubmed/21706236', 'yes', 'yes', 'NA', 1),
(21717192, 'Liang CZ, Zhang JK, Shi Z, Liu B, Shen CQ, Tao HM', 'Matrine induces caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2.', 'Cancer Chemother Pharmacol', '2012', 'Matrine induces caspase-dependent apoptosis in human osteosarcoma cells in vitro and in vivo through the upregulation of Bax and Fas/FasL and downregulation of Bcl-2. Matrine, one of the main active components of extracts from the dry roots of Sophora flavescens, has potent anti-tumor activity in various cancer cell lines. However, the activity of matrine against osteosarcoma remains unclear. In the present study, we examined the effects of matrine on human osteosarcoma cells and explored the underlying mechanism.Four human osteosarcoma cell lines: MG-63, U-2OS, Saos-2, and MNNG/HOS were treated by matrine and subjected to MTT assay, annexin V-FITC/PI double staining, and TUNEL assay. The activation of caspases and the expression of pro-apoptotic and anti-apoptotic factors were examined by qRT-PCR and Western blot. In addition, MNNG/HOS xenograft tumors were established in female nude BALB/c mice, and matrine was intraperitoneally (i.p.) administered to evaluate the anti-cancer capacity of matrine in vivo.We found that matrine inhibited the proliferation and induced apoptosis of the four osteosarcoma cell lines in vitro and induced the activation of caspase-3, -8, and -9 in a dose-dependent manner. Furthermore, the pro-apoptotic factors Bax and Fas/FasL were upregulated, and the anti-apoptotic Bcl-2 was downregulated. More importantly our in vivo, studies showed that administration of matrine decreased tumor growth in a dose-dependent manner. Immunohistochemistry analysis demonstrated the downregulation of Bcl-2 and upregulation of Bax and Fas/FasL in MNNG/HOS tumor tissues following matrine treatment, consistent with the in vitro results.Our results demonstrate that matrine inhibits the proliferation and induces apoptosis of human osteosarcoma cells in vitro and in vivo. The induction of apoptosis appears to occur through the upregulation of Fas/FasL and Bax, downregulation of Bcl-2, and activation of caspase-3, -8, and -9, which then trigger major apoptotic cascades.', 'http://www.ncbi.nlm.nih.gov/pubmed/21717192', 'no', 'no', 'matrine', 7),
(21720717, 'Kim MR, Zhou L, Park BH, Kim JR', 'Induction of G₂/M arrest and apoptosis by sulforaphane in human osteosarcoma U2-OS cells.', 'Mol Med Rep', 'NA', 'Induction of G₂/M arrest and apoptosis by sulforaphane in human osteosarcoma U2-OS cells. Sulforaphane is one of the most abundant isothiocyanates found in certain cruciferous vegetables, particularly broccoli. To date, sulforaphane has gained attention as a chemopreventive compound. The mechanism responsible for the anticancer effects of sulforaphane in osteosarcoma, however, is not clear. In this study, we demonstrate an anti-proliferative mechanism of sulforaphane in human osteosarcoma cells. The treatment of cells with sulforaphane resulted in a concentration- and time‑dependent inhibition of growth and G2/M phase arrest of the cell cycle. This effect was associated with a decrease in protein expression of cyclin A and B1 and their activating partners, cyclin-dependent kinases (CDKs) 1 and 2, with concomitant up-regulation of p21, a CDK inhibitor. Sulforaphane treatment also resulted in apoptosis as evidenced by an increase in annexin V+/propidium iodide- (V+/PI-) cells, the cleavage of 116-kDa poly (ADP-ribose) polymerase (PARP) and ICAD and oligonucleosomal DNA fragmentation. Taken together, these findings indicate that the molecular mechanisms underlying sulforaphane-mediated growth inhibition in U2-OS cells may be the modulation of the cell cycle machinery and the induction of apoptosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21720717', 'no', 'no', 'sulforaphane', 8);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(21750404, 'Wang F, Ke ZF, Sun SJ, Chen WF, Yang SC, Li SH, Mao XP, Wang LT', 'Oncogenic roles of astrocyte elevated gene-1 (AEG-1) in osteosarcoma progression and prognosis.', 'Cancer Biol Ther', '2011', 'Oncogenic roles of astrocyte elevated gene-1 (AEG-1) in osteosarcoma progression and prognosis. Astrocyte elevated gene-1 (AEG-1) is overexpressed in several cancers and plays an important role in cancer progression. However, AEG-1 expression, biological function, and clinical significance in osteosarcoma have not been uncovered. Utilizing manipulated human osteosarcoma cell lines and osteosarcoma tissues, we found that increasing expression of AEG-1 enhanced osteosarcoma cell proliferation and invasion in vitro, and knockdown of AEG-1 significantly attenuated osteosarcoma cell malignancy. Moreover, AEG-1 was overexpressed in osteosarcoma tissues, and overexpression of AEG-1 was strongly associated with gender (p = 0.018), clinical stages (p < 0.001), classification (p < 0.001), metastasis (p = 0.013), differentiation (p < 0.001), and poor survival (p = 0.021). Mechanistic studies conducted in vitro and in vivo revealed that AEG-1-mediated carcinogenesis and invasiveness might be through upregulating MMP-2. Taken together, our data strongly suggest that AEG-1 plays a crucial role in osteosarcoma progression through MMP-2, and AEG-1 could be a useful biomarker for the prediction of osteosarcoma progression and prognosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21750404', 'yes', 'yes', 'NA', 2),
(21751201, 'Moriceau G, Roelofs AJ, Brion R, Redini F, Ebetion FH, Rogers MJ, Heymann D', 'Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth.', 'Cancer', '2012', 'Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth. Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis.The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines.Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used.The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.Copyright © 2011 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21751201', 'no', 'no', 'apomine|lovastatin', 1),
(21751203, 'Hassan SE, Bekarev M, Kim MY, Lin J, Piperdi S, Gorlick R, Geller DS', 'Cell surface receptor expression patterns in osteosarcoma.', 'Cancer', '2012', 'Cell surface receptor expression patterns in osteosarcoma. Although the presence of numerous cell signaling receptors in osteosarcoma is known, their simultaneous characterization has not been performed to date. The current study sought to characterize and quantify the expression of cell surface receptors across a variety of osteosarcoma cell lines.Standard (n = 4) and patient-derived (n = 10) osteosarcoma cell lines were cultured and labeled with antibodies to epidermal growth factor receptor, human epidermal growth factor receptor (HER)-2, HER-3, HER-4, insulin-like growth factor 1 receptor (IGF-1R), IGF-2R, insulin receptor (IR), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, c-Met, fibroblast growth factor receptor (FGFR)-2, FGFR-3, and platelet-derived growth factor receptor (PDGFR)-β. Cell surface examination was performed using flow cytometry, and the geometric fluorescent mean for each receptor was calculated and compared against a positive control.Significant overexpression of IGF-2R was shown in all cell lines, with an average geometric mean above the upper expression quartile. A variable expression pattern was seen for c-Met, PDGFR-β, IR, IGFR-1, HER-2, and VEGFR-3 with expression values for the remaining receptors mainly in the lower quartile. An apparent association between the expression of IGF-1R and HER-2 and between the expression of PDGFR-β and IR was demonstrated.IGF-2R was consistently overexpressed on the cell surface across all tested osteosarcoma cell lines. Substantial, although variable, expression of c-Met, HER-2, IGF-1R, VEGFR-3, IR, and PDGFR-β was demonstrated as well, suggesting that these receptors may contribute to osteosarcoma aggressiveness and biological heterogeneity and may serve as potential targets within a subset of tumors. Associated receptor expression may provide new insight into common regulatory factors or pathways. Targeting either common factors or targeting multiple specific receptors may have therapeutic relevance.Copyright © 2011 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21751203', 'yes', 'no', 'NA', 7),
(21780101, 'Brambilla D, Zamboni S, Federici C, Lugini L, Lozupone F, De Milito A, Cecchetti S, Cianfriglia M, Fais S', 'P-glycoprotein binds to ezrin at amino acid residues 149-242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma.', 'Int J Cancer', '2012', 'P-glycoprotein binds to ezrin at amino acid residues 149-242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma. Overexpression of the mdr1 gene encoding P-glycoprotein (Pgp) exerts a major role in reducing the effectiveness of cytotoxic therapy in osteosarcoma. The interaction between actin and Pgp has been shown to be instrumental in the establishment of multidrug resistance (MDR) in human tumor cells. The cytoskeleton linker ezrin exerts a pivotal role in maintaining the functional connection between actin and Pgp. We investigated the role of ezrin in a human multidrug-resistant osteosarcoma cell line overexpressing Pgp and compared it to its counterpart that overexpresses an ezrin deletion mutant. The results showed that Pgp binds at amino acid residues 149-242 of the N-terminal domain of ezrin. The interaction between ezrin and Pgp occurs in the plasma membrane of MDR cells, where they also co-localize with the ganglioside G(M1) located in lipid rafts. The overexpression of the ezrin deletion mutant entirely restored drug susceptibility of osteosarcoma cells, consistent with Pgp dislocation to cytoplasmic compartments and abrogation of G(M1) /Pgp co-localization at the plasma membrane. Our study provides evidence that ezrin exerts a key role in MDR of human osteosarcoma cells through a Pgp-ezrin-actin connection that is instrumental for the permanence of Pgp into plasma membrane lipid rafts. We also show for the first time that Pgp-binding site is localized to amino acid residues 149-242 of the ezrin Band 4.1, Ezrin/Radixin/Moesin (FERM) domain, thus proposing a specific target for future molecular therapy aimed at counteracting MDR in osteosarcoma patients.Copyright © 2011 UICC.', 'http://www.ncbi.nlm.nih.gov/pubmed/21780101', 'no', 'no', 'NA', 2),
(21801875, 'Kunita A, Kashima TG, Ohazama A, Grigoriadis AE, Fukayama M', 'Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma.', 'Am J Pathol', '2011', 'Podoplanin is regulated by AP-1 and promotes platelet aggregation and cell migration in osteosarcoma. Podoplanin is a type-I transmembrane sialomucin-like protein, which is expressed in a wide range of cell types and is involved in platelet aggregation and tumor metastasis. Here, we investigated the function, regulation, and expression of podoplanin in osteosarcoma. Podoplanin expression was observed in three osteosarcoma cell lines (MG-63, HOS, and U-2 OS) with platelet aggregation-inducing ability, which was blocked by podoplanin small-interfering RNA or a neutralizing antibody. Overexpression of podoplanin in nonmetastatic Dunn osteosarcoma cells promoted cell migration without attenuating cell proliferation. Both podoplanin and TGF-β1 were up-regulated by c-Fos induction in MC3T3-E1 osteoblastic cells, and were highly expressed in c-Fos transgenic mouse osteosarcomas and c-Fos-transformed osteosarcoma cell lines. Immunohistochemistry of human osteosarcoma tissue microarrays (n = 133) showed staining of tumor cells embedded in an excess of irregular neoplastic bone matrix in 100% of tumors undergoing so-called \\normalization/maturation.\\ Podoplanin was also expressed in osteosarcoma subtypes, with 65% of osteoblastic, 100% of chondroblastic, and 79% of fibroblastic tumors. CD44 and pERM immunohistochemistry showed coexpression with podoplanin in both mouse and human osteosarcoma. Podoplanin expression was significantly higher in metastatic osteosarcomas (n = 6) than in primary osteosarcomas (n = 10). Our data suggest that podoplanin, which is not expressed in normal osteoblasts but in osteocytes, is aberrantly expressed in transformed osteoblasts and in osteosarcoma, and is under AP-1 transcriptional control. Thus podoplanin is a candidate molecule for therapeutic targeting.Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21801875', 'yes', 'no', 'NA', 4),
(21805050, 'Liang W, Li X, Li C, Liao L, Gao B, Gan H, Yang Z, Liao L, Chen X', 'Quercetin-mediated apoptosis via activation of the mitochondrial-dependent pathway in MG-63 osteosarcoma cells.', 'Mol Med Rep', 'NA', 'Quercetin-mediated apoptosis via activation of the mitochondrial-dependent pathway in MG-63 osteosarcoma cells. Quercetin (a natural polyphenolic compound) is a polyphenolic flavonoid compound found in a variety of plants. It has been demonstrated to exert cytostatic activity against a variety of human cancer cell lines, including the human osteosarcoma cell line, MG-63. However, its effects on osteosarcoma cell apoptosis are still undefined. The present study was undertaken to examine the effect of quercetin on cell viability, apoptosis and mitochondrial membrane potential, and to determine the molecular mechanism of quercetin-induced apoptosis by investigating the expression of Bcl-2 family proteins (Bcl-2, Bax), cytochrome C, caspase-9 and caspase-3 in MG-63 cells. We found that quercetin suppressed the viability of MG-63 cells in a dose- and time- dependent manner. Furthermore, we observed that quercetin induced the loss of mitochondrial membrane potential, upregulated the expression of the proapoptotic proteins, Bax and cytochrome C, and activated caspase-9 and caspase-3, and downregulated the expression of antiapoptotic protein, Bcl-2. These data suggest that quercetin may induce apoptosis via the mitochondrial-dependent pathway in MG-63 cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/21805050', 'no', 'no', 'quercetin', 5),
(21822121, 'Morales AG, Brassesco MS, Pezuk JA, Oliveira JC, Montaldi AP, Sakamoto-Hojo ET, Scrideli CA, Tone LG', 'BI 2536-mediated PLK1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity.', 'Anticancer Drugs', '2011', 'BI 2536-mediated PLK1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity. Osteosarcoma is the most common primary malignant tumor of bone, which frequently occurs in the second decade of life. Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with chemoresistant or metastatic tumors is still poor. Therefore, there is a need for the development of more efficient therapeutic agents. BI 2536, an innovative selective inhibitor of Polo-like kinase 1, has shown anticancer potential promoting mitotic arrest and apoptosis in a variety of tumor cells, including osteosarcoma. Here, we present more evidence of the antiproliferative effects of BI 2536 on HOS and MG-63 osteosarcoma cell lines. Our results showed that nanomolar concentrations (10, 50, and 100 nmol/l) of the drug significantly decreased cell proliferation and clonogenic capacity, inducing mitotic arrest and aneuploidy. Interestingly, although BI 2536 mediated a moderate increase of apoptosis after 48 h in HOS cells, no increased caspase-3 activity was detected for MG-63 cells. In contrast to previous studies, we show that perturbation of normal mitotic progression by BI 2536 in these osteosarcoma cell lines results in caspase-independent mitotic catastrophe followed by necrosis. Our findings reinforce the likelihood of directing against Polo-like kinase 1 as a therapeutic option in the treatment of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/21822121', 'no', 'no', 'BI 2536', 1),
(21822538, 'Yan X, Feng J, Ye Z, Miao X, Li W, Yang D', 'p53 siRNA inhibits apoptosis of U2OS cells treated with azurin.', 'Mol Med Rep', 'NA', 'p53 siRNA inhibits apoptosis of U2OS cells treated with azurin. The bacterial redox protein azurin selectively induces apoptosis in human osteosarcoma U2OS cells. We constructed a p53 siRNA to test the role that p53 plays in the apoptosis-inducing role of azurin in U2OS cells. Cells treated with p53 siRNA and azurin showed more viable cells, a lower apoptosis rate, lower caspase-3 activity, and up-regulation of bcl-2, downregulation of bax compared to cells treated with negative siRNA and azurin. Cells treated with negative siRNA and azurin yielded positive TUNEL dying, whereas cells treated with p53 siRNA and azurin yielded few positive cells. These results suggested that p53 siRNA was capable of inhibi-ting the apoptosis induced by azurin 2 days after treatment with p53 siRNA and azurin. Azurin may induce apoptosis through combination with p53. The decrease in p53 protein levels did not inhibit cell apoptosis rates, but rather increased these rates in U2OS osteosarcoma cells 3 days after treatment with p53 siRNA. Since U2OS cells are p53 wild-type cancer cells, p53 potentially acts as an oncogene in U2OS osteosarcoma cells. Treatment with azurin may transform the function of p53 from inhibiting to inducing apoptosis.', 'http://www.ncbi.nlm.nih.gov/pubmed/21822538', 'no', 'no', 'azurin', 4),
(21826087, 'Biason P, Hattinger CM, Innocenti F, Talamini R, Alberghini M, Scotlandi K, Zanusso C, Serra M, Toffoli G', 'Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy.', 'Pharmacogenomics J', '2012', 'Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy. The aim of this study was to investigate the role of common polymorphisms in the nucleotide excision repair pathway genes in the tumorigenesis of osteosarcoma and in the response to DNA damaging therapies, such as cisplatin-based neoadjuvant therapy. Excision repair cross-complementing (ERCC) group 2 (XPD; rs13181 and rs1799793), group 5 (XPG; rs17655) and group 1 (XPA; rs3212986 and rs11615) polymorphisms were analyzed in a group of 130 homogenously treated patients with high-grade osteosarcoma, for association with event-free survival (EFS), using the Kaplan-Meier plots and log-rank test. A positive association was observed between both XPD single-nucleotide polymorphisms and an increased EFS (hazards ratio (HR) = 0.34, 95% confidence interval (CI) 0.12-0.98 and HR = 0.19, 95% CI 0.05-0.77, respectively). We had also performed a case-control study for relative risk to develop osteosarcoma. Patients carrying at least one variant allele of XPD rs1799793 had a reduced risk of developing osteosarcoma, compared with wild-type patients (odds ratio = 0.55, 95% CI 0.36-0.84). This study suggests that XPD rs1799793 could be a marker of osteosarcoma associated with features conferring either a better prognosis or a better outcome after platinum therapy, or both.', 'http://www.ncbi.nlm.nih.gov/pubmed/21826087', 'yes', 'yes', 'NA', 3),
(21826611, 'Chen XJ, Duan FD, Zhang HH, Xiong Y, Wang J', 'Sodium selenite-induced apoptosis mediated by ROS attack in human osteosarcoma U2OS cells.', 'Biol Trace Elem Res', '2012', 'Sodium selenite-induced apoptosis mediated by ROS attack in human osteosarcoma U2OS cells. Sodium selenite (Na(2)SeO(3), SSE) is an inorganic Se compound that is widely used in cancer chemoprevention studies. SSE has been shown to have anti-proliferative effects on several types of human cancer cells, but its effect on osteosarcoma cells has thus far not been reported. In this study, the cytotoxic effect of SSE on osteosarcoma cells U2OS was investigated in vitro and found to be higher than on comparable non-cancer cell lines 293 and L6. Treatment with SSE decreased cell growth in a dose- and time-dependent manner and altered cellular morphology. SSE also inhibited cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies, generation of reactive oxygen species (ROS), and accumulation of cells during the advanced phase of apoptosis. SSE-induced apoptosis correlated with the activation of CASP 3, downregulation of BCL-2, and upregulation of P53 and PTEN in U2OS cells. These results indicated that SSE induces apoptosis in U2OS cells mainly through an ROS-mediated caspase pathway. This is the first report to show a possible mechanism of the anti-proliferative effect of SSE for the prevention of osteosarcoma in cell culture models.', 'http://www.ncbi.nlm.nih.gov/pubmed/21826611', 'no', 'no', 'sodium selenite', 4),
(21834878, 'Datsis GA, Berdiaki A, Nikitovic D, Mytilineou M, Katonis P, Karamanos NK, Tzanakakis GN', 'Parathyroid hormone affects the fibroblast growth factor-proteoglycan signaling axis to regulate osteosarcoma cell migration.', 'FEBS J', '2011', 'Parathyroid hormone affects the fibroblast growth factor-proteoglycan signaling axis to regulate osteosarcoma cell migration. Parathyroid hormone (PTH)(1-34), which has been established to have a dual effect on bone metabolism, was recently found to regulate osteosarcoma cell migration. A significant part of the bone anabolic action of PTH(1-34) is attributed to fibroblast growth factor (FGF)-2 stimulation. Furthermore, it was recently suggested that the FGF-proteoglycan axis may form an extracellular matrix-related regulatory feedback loop that controls osteoblastic lineage cell proliferation and execution of the osteogenic program. In this study, we investigated the possible participation of FGF-2 signaling in PTH(1-34)-dependent osteosarcoma cell migration. FGF-2 treatment of osteosarcoma cells resulted in a significant increase (P ≤ 0.01) in MG63 cell migration, similar to that caused by PTH(1-34). mRNA expression analysis of cells treated with PTH(1-34) showed a strong increase in FGF-2 transcript levels (P = 0.0015). Interestingly, the addition of FGF-2 to MG63 cells led to significant downregulation of small leucine-rich proteoglycan biglycan expression at both the mRNA (P ≤ 0.0001) and protein (60%) levels. In order to examine the significance of biglycan on MG63 cell migration, transfection with short interfering RNA specific for biglycan was performed, resulting in a significant increase (P ≤ 0.01) in the migration capacity of biglycan-deficient MG63 cells. In contrast, exogenous human recombinant biglycan strongly inhibited the migration of these cells (P ≤ 0.01). Finally, a direct correlation between PTH(1-34) action and biglycan expression was established by the finding of a significant decrease (P ≤ 0.01) in biglycan transcript levels in PTH(1-34)-treated cells. To summarize, the present study demonstrates a novel cooperative mechanism of PTH(1-34) and FGF-2 action that results in specific alteration of the biglycan extracellular matrix content to regulate osteosarcoma cell migration.© 2011 The Authors Journal compilation © 2011 FEBS.', 'http://www.ncbi.nlm.nih.gov/pubmed/21834878', 'no', 'no', 'NA', 3),
(21843050, 'Luk F, Yu Y, Walsh WR, Yang JL', 'IGF1R-targeted therapy and its enhancement of doxorubicin chemosensitivity in human osteosarcoma cell lines.', 'Cancer Invest', '2011', 'IGF1R-targeted therapy and its enhancement of doxorubicin chemosensitivity in human osteosarcoma cell lines. Type-I insulin-like growth factor receptor (IGF1R) and its signaling play an important role in osteosarcomagenesis, tumor progression, and chemoresistance. The purpose of this study was to investigate both the effect and mechanisms of IGF1R inhibition by tyrphostin AG1024 in the presence or absence of doxorubicin in a panel of six osteosarcoma cell lines and a self-established doxorubicin-resistant cell line. We are the first to indicate that targeting IGF1R together with doxorubicin achieved additive anti-osteosarcoma growth effect, accompanied with increased apoptosis, cytotoxicity, and dual cell cycle arrests. In conclusion, IGF1R inhibition can enhance doxorubicin chemotherapy in some osteosarcoma cell lines.', 'http://www.ncbi.nlm.nih.gov/pubmed/21843050', 'no', 'no', 'tyrphostin AG1024|doxorubicin', 1),
(21843952, 'Whitaker EL, Filippov V, Filippova M, Guerrero-Juarez CF, Duerksen-Hughes PJ', 'Splice variants of mda-7/IL-24 differentially affect survival and induce apoptosis in U2OS cells.', 'Cytokine', '2011', 'Splice variants of mda-7/IL-24 differentially affect survival and induce apoptosis in U2OS cells. Interleukin-24 (mda-7/IL-24) is a cytokine in the IL-10 family that has received a great deal of attention for its properties as a tumor suppressor and as a potential treatment for cancer. In this study, we have identified and characterized five alternatively spliced isoforms of this gene. Several, but not all of these isoforms induce apoptosis in the osteosarcoma cell line U2OS, while none affect the survival of the non-cancerous NOK cell line. One of these isoforms, lacking three exons and encoding the N-terminal end of the mda-7/IL-24 protein sequence, caused levels of apoptosis that were higher than those caused by the full-length mda-7/IL-24 variant. Additionally, we found that the ratio of isoform expression can be modified by the splice factor SRp55. This regulation suggests that alternative splicing of mda-7/IL-24 is under tight control in the cell, and can be modified under various cellular conditions, such as DNA damage. In addition to providing new insights into the function of an important tumor suppressor gene, these findings may also point toward new avenues for cancer treatment.Copyright © 2011 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21843952', 'no', 'no', 'NA', 1),
(21866554, 'Wang YH, Han XD, Qiu Y, Xiong J, Yu Y, Wang B, Zhu ZZ, Qian BP, Chen YX, Wang SF, Shi HF, Sun X', 'Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma.', 'J Surg Oncol', '2012', 'Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma. The aim of this study was to investigate the association of insulin-like growth factor-1 receptor (IGF-1R) with metastasis and prognosis of osteosarcoma patients.RT-PCR and Western blot assays were performed to detect IGF-1R mRNA and protein expression in 26 osteosarcoma and noncancerous bone tissues. Immunohistochemistry was performed to analyze the correlation of IGF-1R expression in 84 osteosarcoma tissues with clinicopathological factors or survival of patients. Lentivirus-mediated RNA interference system was employed to downregulate IGF-1R expression and analyze the effects of IGF-1R downregulation on invasion and metastasis of osteosarcoma cells.The relative levels of IGF-1R mRNA and protein expression were significantly higher in osteosarcoma tissues than in corresponding noncancerous bone tissues. The expression of IGF-1R protein was closely associated with surgical stage and distant metastasis of osteosarcoma patients. Osteosarcoma patients with high IGF-1R expression had poorer survival, and multivariate Cox analyses showed that high IGF-1R expression was an independent prognostic maker. Lentivirus-mediated targeting IGF-1R could significantly inhibit adhesion, migration, invasion, and metastasis of osteosarcoma cells, which might be correlated with of inactivation of Akt signaling pathway.IGF-1R is an independent prognostic marker for osteosarcoma patients and increased expression of this molecular is correlated with metastasis of osteosarcoma.Copyright © 2011 Wiley Periodicals, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/21866554', 'yes', 'yes', 'NA', 1),
(21868524, 'Perez J, Bardin C, Rigal C, Anthony B, Rousseau R, Dutour A', 'Anti-MDR1 siRNA restores chemosensitivity in chemoresistant breast carcinoma and osteosarcoma cell lines.', 'Anticancer Res', '2011', 'Anti-MDR1 siRNA restores chemosensitivity in chemoresistant breast carcinoma and osteosarcoma cell lines. Reversion of chemoresistance by inhibition of P-glycoprotein (P-gp) expression may overcome the chemoresistance observed in many cancer types and may allow for improved therapeutic ratio. We investigated whether siRNA specific for ABCB1 (MDR1) mRNA might restore sensitivity to chemotherapy in tumor cell lines known to overexpress the MDR1 gene.MDR1-expressing tumor cell lines were transiently transfected with anti-MDR1 silencing RNA (siRNA) before exposure to doxorubicin or methotrexate. The capacity of siRNA to reduce cell proliferation and increase the IC₅₀ of the tested chemotherapies was investigated.siRNA down-regulated MDR1 mRNA expression by 50% in breast carcinoma and osteosarcoma cell lines, and significantly inhibited tumor cell proliferation up to 90% (p<0.01), when co-administered with doxorubicin or methotrexate, despite the known chemoresistance of the cell lines. siRNAs reduced the IC₅₀ of doxorubicin and methotrexate by more than 10-fold (p<0.01).These results suggest the potential clinical application of anti-MDR1 siRNA to restore chemosensitivity and possibly improve the therapeutic ratio of these cytotoxic drugs.', 'http://www.ncbi.nlm.nih.gov/pubmed/21868524', 'no', 'no', 'doxorubicin|ethotrexate', 1),
(21874265, 'Wu G, Wei L, Yu A, Zhang M, Qi B, Su K, Hu X, Wang J', 'Vasodilator-stimulated phosphoprotein regulates osteosarcoma cell migration.', 'Oncol Rep', '2011', 'Vasodilator-stimulated phosphoprotein regulates osteosarcoma cell migration. Vasodilator-stimulated phosphoprotein (VASP) has been reported to play an important role in the process of cell migration and tumor metastasis. However, to date, no study has examined VASP expression and its function in osteocarcoma cells. In this study, we analyzed the effect of VASP on osteosarcoma cell migration and the signal transduction pathways involved. We used two osteosarcoma cell strains (Mg-63 and Saos-2 cells) with different metastatic potential. Silencing of VASP gene expression was carried out using RNA interference in these cells. Knockdown of expression at the transcriptional or translational level was determined by RT-PCR or western blot analysis, respectively. The metastatic potential of the tumor cells was determined by a wound healing migration assay. VASP mRNA expression was also determined in 30 human osteosarcoma samples. Furthermore, Rac1 was determined as a regulator of VASP function. RT-PCR and western blotting showed that Mg-63 cells had a significantly higher VASP expression at both the transcriptional and translational levels compared to Saos-2 cells. The wound healing assay revealed that Mg-63 cells had more migratory potential compared to Saos-2 cells. The effect was found to be reversible when VASP was knocked down by siRNA in Mg-63 cells. Specimens from human patients with metastases had higher VASP expression compared to specimens of patients without metastases. Knockdown of Rac1 resulted in inhibition of VASP expression in sarcoma cells. These results suggest that VASP protein regulates osteosarcoma cell migration and metastasis. Rac1 and VASP interaction may be a potential target for osteo-sarcoma treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/21874265', 'no', 'no', 'NA', 2),
(21887680, 'Windsor RE, Strauss SJ, Kallis C, Wood NE, Whelan JS', 'Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study.', 'Cancer', '2012', 'Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma: a pilot study. Osteosarcoma is the most common malignant bone tumor in children and young people. Efficacy of multiagent MAP (methotrexate, doxorubicin [Adriamycin], cisplatin) chemotherapy may be influenced by multiple cellular pathways. This pilot study aimed to investigate the association of 36 candidate genetic polymorphisms in MAP pathway genes with histological response, survival, and grade 3-4 chemotherapy toxicity in osteosarcoma.Blood samples were obtained from 60 patients who had completed MAP chemotherapy. All patients were manually genotyped for 5 polymorphisms. The remaining 31 polymorphisms were genotyped in 50 patients using the Illumina 610-Quad microarray. Associations between candidate polymorphisms and histological response, progression-free survival, and toxicity were estimated using Pearson chi-square and Fisher exact tests, the Kaplan-Meier method, the log-rank test, and the Cox proportional hazards model.Poor histological response was increased in variants of ABCC2 c.24C>T (P = .011) and GSTP1 c.313A>G p.Ile(105)Val (P = .009), whereas MTHFD1 c.1958G>A p.Arg(653)Gln was protective (P = .03). Methotrexate toxicity was increased in variants of MTHFR c.1298A>C p.Glu(429)Ala (P = .038), ABCB1 c.3435T>C Ile(145)Ile (P = .027), and ABCC2 c.3563T>A p.Val(1188)Glu (P = .028). Variants of GSTP1 c.313A>G p.Ile(105)Val were at increased risk of myelosuppression (P = .024) and cardiac damage (P = .008).This pilot study represents the most comprehensive study to date examining the role of genetic polymorphisms in osteosarcoma. Although small and retrospective, it shows that several polymorphisms appear to significantly influence toxicity and clinical outcome. These deserve prospective validation in the hope of optimizing treatment for resistant disease and reducing the late effects burden.Copyright © 2011 American Cancer Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/21887680', 'yes', 'no', 'NA', 4),
(21890444, 'Wu X, Cai ZD, Lou LM, Zhu YB', 'Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients.', 'Cancer Epidemiol', '2012', 'Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients. Nowadays it remains a controversial issue whether a correlation exists between the apoptosis rate of tumor tissue and the prognosis of the patients. The aim of the study is to investigate the relationships of apoptotic genes and apoptotic index of osteosarcoma tissue to prognosis of the patients, meanwhile to explore the valid prognostic biomarkers of osteosarcoma that will enhance efficacy of clinical treatments for osteosarcoma.In our studies, the immunohistochemical ABC and terminal DNA breakpoints in situ 3-hydroxy end labeling (TUNEL) techniques were used to detect the expressions of p53, c-MYC, BCL-2 and apoptotic index in 56 osteosarcoma specimens. The relationships between apoptotic genes expression and apoptotic index in osteosarcoma tissue and their correlations with pathologic classification and prognosis of osteosarcoma cases were analyzed.We found that the expressions of p53, c-MYC, and BCL-2 were negatively correlated with apoptotic index of osteosarcoma tissue, were not correlated with pathological types of osteosarcoma, and were closely related to prognosis of the patients. Moreover, apoptotic index of osteosarcoma tissue was positively correlated with the long term survival of the patients.We concluded that the expressions of p53, c-MYC, BCL-2 protein and apoptotic index could be used as potential biomarks for predicting the progression and prognosis of osteosarcoma, and for optimizing clinical treatments.Copyright Â© 2011 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21890444', 'yes', 'yes', 'NA', 3),
(21901524, 'Yu L, Guo W, Zhao S, Tang J, Liu J', 'Knockdown of Mad2 induces osteosarcoma cell apoptosis-involved Rad21 cleavage.', 'J Orthop Sci', '2011', 'Knockdown of Mad2 induces osteosarcoma cell apoptosis-involved Rad21 cleavage. Besides Mad2''s role in carcinogenesis, recent study has shown that it is essential in cell survival. Here we found that knockdown of Mad2 causes osteosarcoma cell death through apoptosis, with the apoptotic signal resulting from Rad21 cleavage.U2OS and MG63 cells were divided into three groups: the Mad2 siRNA group, mock group and normal control group; the Mad2 siRNA group and mock group are transfected with Mad2 shRNA plasmid and mock plasmid, respectively. G418 was used to increase the transfection efficacy, which was evaluated by GFP fluorescence. Quantitative PCR and Western blotting analyses were used to detect the transcription and expression of Mad2, Rad21 and caspase-3, respectively. Flow cytometry assay using PE-labeled Annexin-V and PI, TUNEL assay and Hoechst 33258 staining were used to evaluate cell apoptosis.We successfully achieved knockdown of Mad2 expression in cancer cells using RNA interference. We observed obvious apoptosis in the Mad2 siRNA group compared with the Mock and control group. We found that the apoptosis induced by Mad2 knockdown correlated with Rad21 cleavage.These results confirmed that knockdown of Mad2 causes osteosarcoma cell death through apoptosis and provides evidence that the apoptotic signal resulted from Rad21 cleavage. This study suggested that Mad2 has potential to be a novel target for cancer therapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/21901524', 'no', 'no', 'NA', 3),
(21925315, 'Williams SA, Maecker HL, French DM, Liu J, Gregg A, Silverstein LB, Cao TC, Carano RA, Dixit VM', 'USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma.', 'Cell', '2011', 'USP1 deubiquitinates ID proteins to preserve a mesenchymal stem cell program in osteosarcoma. Inhibitors of DNA binding (IDs) antagonize basic-helix-loop-helix (bHLH) transcription factors to inhibit differentiation and maintain stem cell fate. ID ubiquitination and proteasomal degradation occur in differentiated tissues, but IDs in many neoplasms appear to escape degradation. We show that the deubiquitinating enzyme USP1 promotes ID protein stability and stem cell-like characteristics in osteosarcoma. USP1 bound, deubiquitinated, and thereby stabilized ID1, ID2, and ID3. A subset of primary human osteosarcomas coordinately overexpressed USP1 and ID proteins. USP1 knockdown in osteosarcoma cells precipitated ID protein destabilization, cell-cycle arrest, and osteogenic differentiation. Conversely, ectopic USP1 expression in mesenchymal stem cells stabilized ID proteins, inhibited osteoblastic differentiation, and enhanced proliferation. Consistent with USP1 functioning in normal mesenchymal stem cells, USP1-deficient mice were osteopenic. Our observations implicate USP1 in preservation of the stem cell state that characterizes osteosarcoma and identify USP1 as a target for differentiation therapy.Copyright © 2011 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21925315', 'no', 'no', 'NA', 4),
(21927024, 'Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry JA, Orkin SH, Mansukhani A, Basilico C', 'Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas.', 'Oncogene', '2012', 'Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.', 'http://www.ncbi.nlm.nih.gov/pubmed/21927024', 'yes', 'no', 'NA', 2),
(21941146, 'Osborne TS, Ren L, Healey JH, Shapiro LQ, Chou AJ, Gorlick RG, Hewitt SM, Khanna C', 'Evaluation of eIF4E expression in an osteosarcoma-specific tissue microarray.', 'J Pediatr Hematol Oncol', '2011', 'Evaluation of eIF4E expression in an osteosarcoma-specific tissue microarray. The ability to define osteosarcoma (OS) patients at greatest risk for metastatic progression and nonresponsiveness to conventional therapy is currently not possible. Such biomarkers are needed to predict overall prognosis, probability of metastases at diagnosis, and response to chemotherapy. The tissue microarray (TMA) serves as a powerful tool for detecting and validating protein biomarkers across a variety of patients. We constructed a novel outcome-linked TMA to add to and address shortcomings of currently available OS tissue resources. To test the use of our TMA, we surveyed the expression of eukaryotic initiation factor 4E (eIF4E) in OS patients using immunohistochemistry. Aberrant regulation of translation initiation is a feature of many cancers. eIF4E is central to initiation of protein synthesis. Its expression and activity have been implicated in tumor formation and potentially malignant and/or metastatic progression in some carcinomas. We found that eIF4E was uniformly expressed in OS patient samples. No association was found between eIF4E and outcome in OS patients. This novel OS TMA provided a facile mechanism to assess the role of a relevant protein biomarker in OS.', 'http://www.ncbi.nlm.nih.gov/pubmed/21941146', 'yes', 'no', 'NA', 1),
(21945933, 'Huang Y, Yang Y, Gao R, Yang X, Yan X, Wang C, Jiang S, Yu L', 'RLIM interacts with Smurf2 and promotes TGF-β induced U2OS cell migration.', 'Biochem Biophys Res Commun', '2011', 'RLIM interacts with Smurf2 and promotes TGF-β induced U2OS cell migration. TGF-β (transforming growth factor-β), a pleiotropic cytokine that regulates diverse cellular processes, has been suggested to play critical roles in cell proliferation, migration, and carcinogenesis. Here we found a novel E3 ubiquitin ligase RLIM which can directly bind to Smurf2, enhancing TGF-β responsiveness in osteosarcoma U2OS cells. We constructed a U2OS cell line stably over-expressing RLIM and demonstrated that RLIM promoted TGF-β-driven migration of U2OS cells as tested by wound healing assay. Our results indicated that RLIM is an important positive regulator in TGF-β signaling pathway and cell migration.Copyright © 2011 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21945933', 'no', 'no', 'NA', 3),
(21951664, 'Sugawara M, Kato N, Tsuchiya T, Motoyama T', 'RUNX2 expression in developing human bones and various bone tumors.', 'Pathol Int', '2011', 'RUNX2 expression in developing human bones and various bone tumors. The heterozygous germline mutation of runt-related protein 2 (RUNX2) causes cleidocranial dysplasia. To clarify the involvement of RUNX2 in human osteogenesis, fetal bones and various bone tumors were immunohistochemically examined. During both membranous and endochondral ossification in the fetus (n= 8), RUNX2 was expressed not only in osteoblastic cells but also in surrounding mesenchymal cells and early stage chondrocytes. Such an expression pattern was recapitulated in bone tumors: RUNX2 was unequivocally expressed in osteosarcoma (n= 20) and fibrous dysplasia (n= 10), regardless of the site of occurrence, cell morphology or amount of neoplastic osteoid. RUNX2 expression was limited to less differentiated cells in chondrogenic tumors (n= 20). We further analyzed whether RUNX2 expression was regulated by bone morphogenetic protein-2 (BMP-2), which is critical for osteoblastic differentiation. With real-time polymerase chain reaction, the RUNX2 mRNA level was correlated with BMP-2 mRNA level, and both levels were significantly higher in three osteosarcoma cell lines than in three chondrosarcoma cell lines. With treatment of recombinant BMP-2, the RUNX2 mRNA level was significantly altered in these cell lines. RUNX2 expression is constitutive in developing and neoplastic human osteogenesis, and is most likely to be regulated by BMP-2.© 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.', 'http://www.ncbi.nlm.nih.gov/pubmed/21951664', 'yes', 'no', 'NA', 2),
(21959981, 'Montanini L, Lasagna L, Barili V, Jonstrup SP, Murgia A, Pazzaglia L, Conti A, Novello C, Kjems J, Perris R, Benassi MS', 'MicroRNA cloning and sequencing in osteosarcoma cell lines: differential role of miR-93.', 'Cell Oncol (Dordr)', '2012', 'MicroRNA cloning and sequencing in osteosarcoma cell lines: differential role of miR-93. Studies show that abnormalities in non-coding genes can contribute to carcinogenesis; microRNA levels may modulate cancer growth and metastatic diffusion.MicroRNA libraries were built and sequenced from two osteosarcoma cell lines (MG-63 and 143B), which differ in proliferation and transmigration. By cloning and transfection, miR-93, expressed in both cell lines, was then investigated for its involvement in osteosarcoma progression.Six of the 19 miRNA identified were expressed in both cell lines with higher expression levels of miR-93 in 143B and in primary osteosarcoma cultures compared to normal osteoblasts. Interestingly, levels of miR-93 were significantly higher in metastases from osteosarcoma than in paired primary tumours. When 143B and MG-63 were transfected with miR-93, clones appeared to respond differently to microRNA overexpression. Ectopic expression of miR-93 more significantly increased cell proliferation and invasivity in 143B than in MG-63 clones. Furthermore, increased mRNA and protein levels of E2F1, one of the potential miR-93 targets, were seen in osteosarcoma cellular clones and its involvement in 143B cell proliferation was confirmed by E2F1 silencing.Although further studies are needed to evaluate miRNA involvement in osteosarcoma progression, miR-93 overexpression seems to play an important role in osteosarcoma cell growth and invasion.', 'http://www.ncbi.nlm.nih.gov/pubmed/21959981', 'no', 'no', 'NA', 2),
(21963453, 'Yang H, Zhang Y, Zhou Z, Jiang X, Shen A', 'Snail-1 regulates VDR signaling and inhibits 1,25(OH)-D₃ action in osteosarcoma.', 'Eur J Pharmacol', '2011', 'Snail-1 regulates VDR signaling and inhibits 1,25(OH)-D₃ action in osteosarcoma. Previous research has shown that vitamin D could suppress proliferation, migration and invasion of cancers, but the effects of vitamin D may be related to the expression of Snail-1, which could inhibit the expression of the vitamin-D gene receptor (VDR). Snail-1 is overexpressed in osteosarcoma, this study was conducted to determine whether inhibiting Snail-1 could increase the role of vitamin D as an anti- osteosarcoma agent. We used stable transfection of the SaOS₂ cell line as in vitro model to study the effect of 1,25(OH)-D₃, which is the most active metabolite of vitamin D. The in vitro antiproliferative, pro-apoptotic and inhibiting of invasion effects were examined. The effects of 1,25(OH)-D₃ on the expression of β-catenin signaling pathways were also studied. Then in vivo antiproliferative effect of 1,25(OH)-D₃ was also detected in nude mice injected with either mock-infected or Snail-1 SaOS₂ cells. We found that inhibition of Snail-1 signaling by transfection could increase the expression of VDR, enhance the anti-proliferative activity of 1,25(OH)-D₃ in osteosarcoma cells, and induce apoptosis and lower invasion in vitro. The effect of 1,25(OH)-D₃ was also associated with decreased expression of β-catenin signaling, which is related to VDR signaling. In vivo, the effect of antiproliferative was higher in mice injected with either Snail-1-infected cells than with mock-infected cells. Our findings suggest that canonical Snail-1/VDR/β-catenin signaling reflects an important underlying mechanism of osteosarcoma progression. Therefore, strategies to suppress Snail-mediated signaling may lead to the better action of 1,25(OH)-D₃ as an anti osteosarcoma treatment.Copyright © 2011 Elsevier B.V. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21963453', 'no', 'no', 'vitamin D', 3),
(21964477, 'Chen L', 'Okadaic acid induces apoptosis through the PKR, NF-κB and caspase pathway in human osteoblastic osteosarcoma MG63 cells.', 'Toxicol In Vitro', '2011', 'Okadaic acid induces apoptosis through the PKR, NF-κB and caspase pathway in human osteoblastic osteosarcoma MG63 cells. Okadaic acid (OA) is the major component of diarrheic shellfish poisoning toxins and a potent inhibitor of protein phosphatase 1 and 2A. However, the underlying regulatory mechanisms involved in OA-induced cell death are not well understood. In the present study, we examined the effects of OA on apoptosis of MG63 cells by characterizing apoptotic morphological changes of the cells and DNA fragmentation. The roles of double-stranded RNA-dependent protein kinase (PKR), nuclear factor-κB (NF-κB) and caspase in OA-mediated apoptosis in MG63 cells were also examined. Results showed that OA induced cytotoxicity and apoptosis in MG63 cells at IC50 of 75 nM. A functional PKR pathway is required to induce apoptosis in response to OA treatment. Blockade of NF-κB by ammonium pyrrolidinedithiocarbamate (PDTC) resulted in down-regulation of apoptosis. The caspase-3 and caspase-8 inhibitors blocked apoptosis in MG63 cells. In conclusion, our results imply that OA can induce MG63 cell apoptosis through the PKR, NF-κB and caspase pathway.Copyright © 2011 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/21964477', 'no', 'no', 'okadaic acid', 3),
(21986150, 'Qu Y, Xu J, Jiang T, Zhao H, Gao Y, Zheng C, Shi X', 'Difference in pre- and postchemotherapy vascular endothelial growth factor levels as a prognostic indicator in osteosarcoma.', 'J Int Med Res', '2011', 'Difference in pre- and postchemotherapy vascular endothelial growth factor levels as a prognostic indicator in osteosarcoma. This retrospective analysis examined the difference in pre- and postchemotherapy levels of vascular endothelial growth factor (VEGF) as an indicator of osteosarcoma prognosis. VEGF protein levels were assessed immunohistochemically in primary tumour samples from 61 osteosarcoma patients diagnosed between February 2001 and July 2005. The difference in pre- and postchemotherapy VEGF protein reduction levels was categorized into weak (23 patients) and strong (38 patients). The 5-year survival rate was significantly lower in the weak VEGF reduction group (34.8%) than in the strong VEGF reduction group (73.7%). The weak VEGF reduction group had significantly higher rates of metastasis and recurrence. Multivariate analysis confirmed that the change in VEGF was an independent and significant factor for predicting a good prognosis. The analysis of VEGF will enable clinicians to tailor surgery and chemotherapy regimens more appropriately, earlier in the disease process.', 'http://www.ncbi.nlm.nih.gov/pubmed/21986150', 'yes', 'yes', 'NA', 1);

INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(22147650, 'Sollazzo V, Galasso M, Volinia S, Carinci F', 'Prion proteins (PRNP and PRND) are over-expressed in osteosarcoma.', 'J Orthop Res', '2012', 'Prion proteins (PRNP and PRND) are over-expressed in osteosarcoma. Although osteosarcoma is the most common bone malignancy, the molecular and cellular mechanisms influencing its pathogenesis have remained elusive. Prion proteins (PRNP and PRND), known mostly for its involvement in neurodegenerative spongiform encephalopathies, have been recently demonstrated to be involved in resistance to apoptosis, tumorigenesis, proliferation, and metastasis. The main aim of research was to study whether prion proteins were over-expressed in human osteosarcoma, and if prion proteins could have a role also in osteosarcomas. We evaluated differential gene expression between 22 cases of osteosarcoma and 40 cases of normal bone specimens through cDNA microarray analysis spanning a substantial fraction of the human genome. PRNP and PRND are significantly over-expressed in osteosarcoma. PRNP and PRND appear involved with some important genes related to tumorigenesis and apoptosis. PRNP is linked to PTK2, RBBP9, and TGFB1 while PRND is linked to TNFSF10, BCL2A1, NFKB2, and TP53RK. Increased expression on Affymetrix arrays of prion proteins seems to be associated with the development of osteosarcoma. Prions seem to induce a negative regulation of apoptosis, thus promoting osteosarcoma development and progression. Osteosarcoma is a very aggressive tumor and even after modern chemotherapy and excision of tumors efforts are needed to improve clinical outcome. Since Prion proteins seem to be related to osteosarcoma development, their inhibition could represent a new approach to the molecular treatment of osteosarcoma.Copyright © 2011 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/22147650', 'yes', 'no', 'NA', 9),
(22154052, 'Tesser-Gamba F, Petrilli AS, de Seixas Alves MT, Filho RJ, Juliano Y, Toledo SR', 'MAPK7 and MAP2K4 as prognostic markers in osteosarcoma.', 'Hum Pathol', '2012', 'MAPK7 and MAP2K4 as prognostic markers in osteosarcoma. Osteosarcoma is a class of cancer originating from the bone, affecting mainly children and young adults. Cytogenetic studies showed the presence of rearrangements and recurrent gains in specific chromosomal regions, indicating the possible involvement of genes located in these regions during the pathogenesis of osteosarcoma. These studies investigated expression of 10 genes located in the chromosomal region involved in abnormalities in osteosarcoma, 1p36, 17p, and chromosome 19. The purpose of this study was to investigate the expression profile of genes located in regions involved in chromosomal rearrangements in osteosarcoma. We used quantitative real-time polymerase chain reaction to investigate the expression of 10 genes located in 1p36.3 (MTHFR, ERRFI1, FGR, E2F2), 17p (MAPK7, MAP2K4), and chromosome 19 (BBC3, FOSB, JUND, and RRAS), in 70 samples taken from 30 patients (30 prechemotherapy, 30 postchemotherapy, and 10 metastases specimens) and 10 healthy bones as a control sample. The most interesting results showed a strong association between the expression levels of MAPK7 and MAP2K4 genes and clinical parameters of osteosarcoma. Overexpression of these genes was significantly associated to a poor response to treatment (P = .0001 and P = .0049, respectively), tumor progression, and worse overall survival (P = .0052 and P = .0085, respectively), suggesting that MAPK7 and MAP2K4 could play an important role in osteosarcoma tumorigenesis. Thus, these genes could be good markers in assessing response to treatment and development of osteosarcoma.Copyright © 2012 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22154052', 'yes', 'yes', 'NA', 2),
(22158627, 'van der Deen M, Akech J, Lapointe D, Gupta S, Young DW, Montecino MA, Galindo M, Lian JB, Stein JL, Stein GS, van Wijnen AJ', 'Genomic promoter occupancy of runt-related transcription factor RUNX2 in Osteosarcoma cells identifies genes involved in cell adhesion and motility.', 'J Biol Chem', '2012', 'Genomic promoter occupancy of runt-related transcription factor RUNX2 in Osteosarcoma cells identifies genes involved in cell adhesion and motility. Runt-related transcription factors (RUNX1, RUNX2, and RUNX3) are key lineage-specific regulators of progenitor cell growth and differentiation but also function pathologically as cancer genes that contribute to tumorigenesis. RUNX2 attenuates growth and stimulates maturation of osteoblasts during bone formation but is also robustly expressed in a subset of osteosarcomas, as well as in metastatic breast and prostate tumors. To assess the biological function of RUNX2 in osteosarcoma cells, we examined human genomic promoter interactions for RUNX2 using chromatin immunoprecipitation (ChIP)-microarray analysis in SAOS-2 cells. Promoter binding of both RUNX2 and RNA polymerase II was compared with gene expression profiles of cells in which RUNX2 was depleted by RNA interference. Many RUNX2-bound loci (1550 of 2339 total) exhibit promoter occupancy by RNA polymerase II and contain the RUNX consensus motif 5''-((T/A/C)G(T/A/C)GG(T/G). Gene ontology analysis indicates that RUNX2 controls components of multiple signaling pathways (e.g. WNT, TGFβ, TNFα, and interleukins), as well as genes linked to cell motility and adhesion (e.g. the focal adhesion-related genes FAK/PTK2 and TLN1). Our results reveal that siRNA depletion of RUNX2, PTK2, or TLN1 diminishes motility of U2OS osteosarcoma cells. Thus, RUNX2 binding to diverse gene loci may support the biological properties of osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/22158627', 'no', 'no', 'NA', 3),
(22173290, 'Baumhoer D, Smida J, Zillmer S, Rosemann M, Atkinson MJ, Nelson PJ, Jundt G, von Luettichau I, Nathrath M', 'Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma.', 'Mod Pathol', '2012', 'Strong expression of CXCL12 is associated with a favorable outcome in osteosarcoma. Hematogenous spread determines the outcome of osteosarcoma (OS) patients, but the pathogenesis of developing metastatic disease is still unclear. Chemokines are critical regulators of cell trafficking and adhesion, and have been reported to be aberrantly expressed and to correlate with an unfavorable prognosis and metastatic spread in several malignant tumors. The chemokine receptors CXCR4 and CXCR7 together with their common ligand CXCL12 form one of the most important chemokine axes in this context. To investigate a potential role of these chemokines in OSs, we analyzed their expression in a series of 223 well-characterized and pretherapeutic OS samples. Interestingly, we found the expression of CXCL12 and CXCR4 to correlate with a better long-term outcome and with a lower prevalence of metastases. These findings suggest a distinct role of CXCR4/CXCR7/CXCL12 signaling in the tumors of bone, as has also been previously described in acute leukemia. As many malignant tumors metastasize to bone, and tumor cells are thought to be directed to bone in response to CXCL12, OS cells expressing both CXCL12 and the corresponding receptors might be detained at their site of origin. The disruption of CXCR4/CXCR7/CXCL12 signaling could therefore be crucial in OSs for the migration of tumor cells from bone into circulation and for developing systemic disease.', 'http://www.ncbi.nlm.nih.gov/pubmed/22173290', 'yes', 'yes', 'NA', 3),
(22173710, 'Rainusso N, Brawley VS, Ghazi A, Hicks MJ, Gottschalk S, Rosen JM, Ahmed N', 'Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma.', 'Cancer Gene Ther', '2012', 'Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Despite radical surgery and multi-agent chemotherapy, less than one third of patients with recurrent or metastatic osteosarcoma (OS) survive. The limited efficacy of current therapeutic approaches to target tumor-initiating cells (TICs) may explain this dismal outcome. The purpose of this study was to assess the impact of modified T cells expressing a human epidermal growth factor receptor (HER2)-specific chimeric antigen receptor in the OS TIC compartment of human established cell lines. Using the sarcosphere formation assay, we found that OS TICs were resistant to increasing methotrexate concentrations. In contrast, HER2-specific T cells decreased markedly sarcosphere formation capacity and the ability to generate bone tumors in immunodeficient mice after orthotopic transplantation. In vivo, administration of HER2-specific T cells significantly reduced TICs in bulky tumors as judged by decreased sarcosphere forming efficiency in OS cells isolated from explanted tumors. We demonstrate that HER2-specific T cells target drug resistant TICs in established OS cell lines, suggesting that incorporating immunotherapy into current treatment strategies for OS has the potential to improve outcomes.', 'http://www.ncbi.nlm.nih.gov/pubmed/22173710', 'no', 'no', 'NA', 1),
(22179790, 'Si H, Peng C, Li J, Wang X, Zhai L, Li X, Li J', 'RNAi-mediated knockdown of ERK1/2 inhibits cell proliferation and invasion and increases chemosensitivity to cisplatin in human osteosarcoma U2-OS cells in vitro.', 'Int J Oncol', '2012', 'RNAi-mediated knockdown of ERK1/2 inhibits cell proliferation and invasion and increases chemosensitivity to cisplatin in human osteosarcoma U2-OS cells in vitro. Osteosarcoma is the most common primary malignancy of the bone. There have been some advances in surgical and chemotherapeutic strategies, but it is still a tumor with a high mortality rate in children and young adults. Mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) pathway plays an essential role in the development and progression of various tumors. ERK1/2 is a key component of this pathway and hyperactivated in different tumors including osteosarcoma. This study aimed to investigate whether downregulation of ERK1/2 by siRNA (small interfering RNA) could inhibit cell proliferation and invasion and increase chemosensitivity to cisplatin in human osteosarcoma U2-OS cells in vitro. Results showed that the downregulation of ERK1/2 expression by siRNA in human osteosarcoma cells significantly inhibited cell proliferation and invasion in vitro. Furthermore, ERK1/2 knockdown led to cell arrest in the G1/G0 phase of the cell cycle, and eventual apoptosis and chemosensitivity enhancement in tumor cells. Our data reveal that RNAi-mediated downregulation of ERK1/2 expression can lead to potent antitumor activity and chemosensitizing effects in human osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22179790', 'no', 'no', 'cisplatin', 2),
(22186140, 'Huang G, Nishimoto K, Zhou Z, Hughes D, Kleinerman ES', 'miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression.', 'Cancer Res', '2012', 'miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. The ability of osteosarcoma cells to form lung metastases has been inversely correlated to cell surface Fas expression. Downregulation of Fas allows osteosarcoma cells to circumvent FasL-mediated apoptosis upon entrance into the FasL(+) lung microenvironment. However, the mechanism of Fas regulation remains unclear. Here, we show that miRNA plays a role in the downregulation of Fas expression in osteosarcoma. Expression levels of several members of the miR-17-92 cluster including miR-20a and miR-19a were found to be higher in metastatic low-Fas-expressing LM7 cells than in the parental nonmetastatic high-Fas-expressing SAOS-2 cells. We also found an inverse correlation between Fas and miR-20a expression in all 8 cell lines derived from patient samples. Overexpression of miR-20a consistently resulted in the downregulation of Fas expression in SAOS-2 cells and thus in decreased sensitivity to FasL. Conversely, inhibiting miR-20a in LM7 cells increased Fas expression and their sensitivity to FasL. Mice injected with LM7 stably transfected with anti-miR-20a had fewer metastases than those with control plasmids. Taken together, our findings suggest that miR-20a, encoded by miR-17-92, downregulates Fas expression in osteosarcoma, thus contributing to the metastatic potential of osteosarcoma cells by altering the phenotype and allowing survival in the FasL(+) lung microenvironment.', 'http://www.ncbi.nlm.nih.gov/pubmed/22186140', 'no', 'no', 'NA', 4),
(22202598, 'Baumhoer D, Elsner M, Smida J, Zillmer S, Rauser S, Schoene C, Balluff B, Bielack S, Jundt G, Walch A, Nathrath M', 'CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients.', 'Oncotarget', '2011', 'CRIP1 expression is correlated with a favorable outcome and less metastases in osteosarcoma patients. Predicting the clinical course of osteosarcoma patients is a crucial prerequisite for a better treatment stratification in these highly aggressive neoplasms of bone. In search of new and reliable biomarkers we recently identified cysteine-rich intestinal protein 1 (CRIP1) to have significant prognostic impact in gastric cancer and therefore decided to investigate its role also in osteosarcoma. For this purpose we analyzed 223 pretherapeutic and well characterized osteosarcoma samples for their immunohistochemical expression of CRIP1 and correlated our findings with clinico-pathological parameters including follow‑up, systemic spread and response to chemotherapy. Interestingly and contrarily to gastric cancer, we found CRIP1 expression more frequently in patients with long‑term survival (10-year survival 73% in positive vs. 54% in negative cases, p = 0.0433) and without metastases (p = 0.0108) indicating a favorable prognostic effect. CRIP1 therefore seems to represent a promising new biomarker in osteosarcoma patients which should be considered for a prospective validation.', 'http://www.ncbi.nlm.nih.gov/pubmed/22202598', 'yes', 'yes', 'NA', 1),
(22205265, 'Cai X, Yang M', 'The functional MDM2 T309G genetic variant but not P53 Arg72Pro polymorphism is associated with risk of sarcomas: a meta-analysis.', 'J Cancer Res Clin Oncol', '2012', 'The functional MDM2 T309G genetic variant but not P53 Arg72Pro polymorphism is associated with risk of sarcomas: a meta-analysis. The P53-MDM2 pathway plays a central role in sarcoma pathogenesis. Functional P53 Arg72Pro and MDM2 T309G single-nucleotide polymorphisms (SNP) are considered to have significant effects on risk of sarcomas.Several molecular epidemiology studies have evaluated how these genetic variants are involved in sarcoma development, but the conclusions are inconsistent. Therefore, we conducted this meta-analysis to systematically examine the association between these functional SNPs and sarcoma risk.There are four studies eligible for P53 Arg72Pro SNP (466 sarcoma patients and 552 controls), and three studies for MDM2 T309G SNP (355 sarcoma patients and 645 controls). Pooled odds ratios were appropriately calculated using either fixed-effect model or random-effect model. We did not find a significant association between P53 Arg72Pro polymorphism and sarcoma risk. However, in a stratified analysis, a statistically significant correlation between this SNP and osteosarcoma risk was observed. For MDM2 T309G variant, pooled results from the meta-analysis indicate that carriers of TG and GG genotypes showed a 34% increased risk to develop sarcomas compared to TT carriers.These results suggest that the functional MDM2 T309G genetic variant may play a more important role in carcinogenesis of sarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22205265', 'yes', 'no', 'NA', 2),
(22212432, 'Chen Z, Huang C, Yang YL, Ding Y, Ou-Yang HQ, Zhang YY, Xu M', 'Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells.', 'Acta Pharmacol Sin', '2012', 'Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells. To investigate the molecular mechanisms underlying the antitumor activity of cepharanthine (CEP), an alkaloid extracted from Stephania cepharantha Hayata.Human osteosarcoma cell line SaOS2 was used. MTT assay, Hoechst 33342 nuclear staining, flow cytometry, Western blotting and nude mouse xenografts of SaOS2 cells were applied to examine the antitumor activity of CEP in vitro and in vivo. The expression levels of STAT3 and its downstream signaling molecules were measured with Western blotting and immunochemistry analysis. The activity of STAT3 was detected based on the phosphorylation level of STAT3, luciferase gene reporter assay and translocation of STAT3 to the nucleus.Treatment of SaOS2 cells with CEP (2.5-20 μmol/L) inhibited the cell growth in a concentration- and time-dependent manner. CEP (10 μmol/L) caused cell cycle arrest at G(1) phase and induced apoptosis of SaOS2 cells. CEP (10 and 15 μmol/L) significantly decreased the expression of STAT3 in SaOS2 cells. Furthermore, CEP (5 and 10 μmol/L) significantly inhibited the expression of target genes of STAT3, including the anti-apoptotic gene Bcl-xL and the cell cycle regulators c-Myc and cyclin D1. In nude mouse xenografts of SaOS2 cells, CEP (20 mg·kg(-1)·d(-1), ip for 19 d) significantly reduced the volume and weight of the tumor.Our findings suggest that inhibition of STAT3 signaling pathway is involved in the anti-tumor activity of CEP.', 'http://www.ncbi.nlm.nih.gov/pubmed/22212432', 'no', 'no', 'cepharanthine', 4),
(22213004, 'Shen A, Zhang Y, Yang H, Xu R, Huang G', 'Overexpression of ZEB1 relates to metastasis and invasion in osteosarcoma.', 'J Surg Oncol', '2012', 'Overexpression of ZEB1 relates to metastasis and invasion in osteosarcoma. This study aimed to investigate the expression of ZEB1 in osteosarcoma tissues and to discuss the relationship between ZEB1 expression and osteosarcoma metastasis.Using RT-PCR and Western blotting, the mRNA and protein expressions of ZEB1 in the osteosarcoma and normal bone tissues were detected. Using the RNA interference technique, the expression of ZEB1 in the human osteosarcoma MG-63 cell line was downregulated, and the changes in the invasion of MG-63 cells were examined.The positive mRNA expression rate of ZEB1 in the osteosarcoma tissues was significantly higher than that in normal bone tissue (P < 0.05). The protein expression level of ZEB1 in the sarcoma tissues from patients with positive lung metastasis was significantly higher than that from patients without lung metastasis (P < 0.05). After the transfection of ZEB1 siRNA into the MG-63 cells, the protein expression of ZEB1 was significantly reduced (P < 0.05), and the number of cells that passed through the Transwell chamber was significantly lower than that in the non-transfected control group as well as the transfected control group (P < 0.05).The overexpression of ZEB1 in osteosarcoma may be related to the carcinogenesis and development as well as metastasis and invasion of osteosarcoma.Copyright © 2011 Wiley Periodicals, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/22213004', 'yes', 'yes', 'NA', 1),
(22213073, 'Kim SM, Lee H, Park YS, Lee Y, Seo SW', 'ERK5 regulates invasiveness of osteosarcoma by inducing MMP-9.', 'J Orthop Res', '2012', 'ERK5 regulates invasiveness of osteosarcoma by inducing MMP-9. The purpose of this study is to determine the role of ERK5 in cellular invasion of osteosarcoma (OS). The human OS cell line (MG63, SaOS, and U2OS) and primary OS cells were used for the study. The expression of ERK5 and MMP-9 in each cell was examined by western blot or RT-PCR. To evaluate the biological role of ERK5, proliferation assay (MTT) and invasion assay (BD Matrigel™) were performed after silencing ERK5 using siRNA. MMPs expressions were analyzed using RT-PCR and zymography after silencing ERK5. ERK5 was distinctly overexpressed in U2OS and primary OS cell. Both of them also expressed MMP-9, which was not shown in MG63 and SaOS in RT-PCR. ERK5 silencing did not suppress the proliferation of OS cells. However, ERK5 silencing significantly reduced the number of invading cells in invasion assay. The expression of MMP-9 was specifically reduced after silencing ERK5. The zymography showed that the enzyme activity of MMP-9 was also reduced after ERK5 suppression. The expression of ERK5 regulates the invasion of OS cells by inducing MMP-9 expression. Therefore, ERK5 may be a new therapeutic target in invasive OS expressing MMP-9.Copyright © 2011 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/22213073', 'yes', 'no', 'NA', 2),
(22215309, 'Li Z, Liao Q, Wu Y, Liao M, Hao Y, Zhang S, Song S, Li B, Zhang YD', 'Upregulation of a disintegrin and metalloprotease 8 influences tumor metastasis and prognosis in patients with osteosarcoma.', 'Pathol Oncol Res', '2012', 'Upregulation of a disintegrin and metalloprotease 8 influences tumor metastasis and prognosis in patients with osteosarcoma. To investigate the clinicopathological and prognostic value of a disintegrin and metalloprotease 8 (ADAM8) in osteosarcoma. ADAM8 expression in osteosarcoma tissues was examined by immunohistochemistry in 69 patients. ADAM8 was positively expressed in 61 of 69 (88.4%) osteosarcoma specimens with cytoplasmic staining, and also increased in the specimens with recurrence (P = 0.008) and metastasis (P = 0.002). Patients with strong ADAM8 expression had significantly poorer overall survival (OS) and disease-free survival (DFS) (both P < 0.001) when compared with the patients with the weak expression of ADAM8. On multivariate analysis, ADAM8 expression was found to be an independent prognostic factor for both OS (P < 0.001) and DFS (P < 0.001). Our results suggest for the first time that ADAM8 might be applied as a novel marker for the prediction of recurrence and metastasis potency and a significant indicator of poor prognosis for patients with osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22215309', 'yes', 'yes', 'NA', 1),
(22227330, 'Zhang X, Liu Z, Xu B, Sun Z, Gong Y, Shao C', 'Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization.', 'Eur J Pharmacol', '2012', 'Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization. Identification of natural products that have antitumor activity is invaluable to the chemoprevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. In this report we studied the effects of neferine, a major alkaloid component in lotus embryos, on human osteosarcoma cells and the underlying mechanisms. We found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell cycle arrest at G1. The induction of G1 arrest was p21(WAF1/CIP1)-dependent, but was independent of p53 or RB (retinoblastoma-associated protein). The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. We examined four kinases that are known to affect the stabilization of p21, and found that p38 MAPK and JNK were activated by neferine. However, only SB203580 (an inhibitor of p38), but not SP600125 (the inhibitor of JNK), can attenuate the up-regulation of p21 in response to neferine. Furthermore, the p21-stabilizing effect of neferine was abolished when p38 was silenced by RNA interference. Finally, we showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Our results for the first time showed a direct antitumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit.Copyright © 2011 Elsevier B.V. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22227330', 'no', 'no', 'neferine|SB203580|SP600125', 3),
(22231496, 'Gu S, He J', 'Daphnoretin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells.', 'Molecules', '2012', 'Daphnoretin induces cell cycle arrest and apoptosis in human osteosarcoma (HOS) cells. In this study antiproliferation, cell cycle arrest and apoptosis induced by daphnoretin in human osteosarcoma (HOS) cells were investigated. Antiproliferative activity was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC(50) value of daphnoretin was 3.89 μM after 72 h treatment. Induction of apoptosis was evidenced by apoptotic body appearance and Annexin V-FITC/PI apoptosis detection kit. Flow cytometric analysis indicated daphnoretin arrested the cell cycle in the G2/M phase. Western-blot assay showed that the G2/M phase arrest was accompanied by down-regulation of cdc2, cyclin A and cyclin B1. Moreover, daphnoretin inhibited Bcl-2 expression and induced Bax expression to desintegrate the outer mitochondrial membrane and causing cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascade. Our results demonstrated that daphnoretin caused death of HOS cells by blocking cells successively in G2/M phases and activating the caspase-3 pathway.', 'http://www.ncbi.nlm.nih.gov/pubmed/22231496', 'no', 'no', 'daphnoretin', 8),
(22245111, 'Bennani-Baiti IM, Machado I, Llombart-Bosch A, Kovar H', 'Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing''s sarcoma, osteosarcoma, and rhabdomyosarcoma.', 'Hum Pathol', '2012', 'Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed and is an epigenetic drug target in chondrosarcoma, Ewing''s sarcoma, osteosarcoma, and rhabdomyosarcoma. Lysine-specific demethylase 1 (GeneID 23028), a flavin-dependent monoamine oxidoreductase and a histone demethylase, serves as an epigenetic coregulator of transcription. Lysine-specific demethylase 1 is up-regulated in neuroblastoma and in bladder, breast, colorectal, gastric, lung, and neuroendocrine cancers, and its overexpression drives the cell cycle of otherwise nontransformed human cells, suggesting oncogenic properties. Lysine-specific demethylase 1 was recently reported to be also overexpressed in several different mesenchymal tumors. We investigated lysine-specific demethylase 1 expression in over 500 sarcomas by gene expression profiling and tissue microarray-coupled immunohistochemical analyses and confirmed lysine-specific demethylase 1 overexpression in rhabdomyosarcoma and synovial sarcoma. We also show for the first time that lysine-specific demethylase 1 is also overexpressed in chondrosarcoma, Ewing''s sarcoma, and osteosarcoma wherein it localizes in cell nuclei. We further show that a US Food and Drug Administration-approved drug that inhibits lysine-specific demethylase 1 also inhibits chondrosarcoma, Ewing''s sarcoma, osteosarcoma, and rhabdomyosarcoma cell growth in vitro. These data suggest that lysine-specific demethylase 1 plays a role in sarcoma pathology and that lysine-specific demethylase 1 inhibition strategies might represent a novel means to inhibiting growth of lysine-specific demethylase 1-overexpressing sarcomas.Copyright © 2012 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22245111', 'yes', 'no', 'NA', 1),
(22246399, 'Wu G, Chen X, Peng J, Cai Q, Ye J, Xu H, Zheng C, Li X, Ye H, Liu X', 'Millimeter wave treatment induces apoptosis via activation of the mitochondrial-dependent pathway in human osteosarcoma cells.', 'Int J Oncol', '2012', 'Millimeter wave treatment induces apoptosis via activation of the mitochondrial-dependent pathway in human osteosarcoma cells. Millimeter wave (MW) is an electromagnetic wave with a wavelength between 1 and 10 mm and a frequency of 30-300 GHz that causes multiple biological effects and has been used as a major component in physiotherapies for the clinical treatment of various types of diseases including cancers. However, the precise molecular mechanism of the anticancer activity of millimeter wave remains to be elucidated. In the present study, we investigated the cellular effects of the MW in the U-2OS human osteosarcoma cell line. Our results showed that MW induced cell morphological changes and reduced cell viability in a dose- and time-dependent manner suggesting that MW inhibited the growth of U-2OS cells as demonstrated. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. In addition, MW treatment caused loss of plasma membrane asymmetry, release of cytochrome c, collapse of mitochondrial membrane potential, activation of caspase-9 and -3, and increase of the ratio of pro-apoptotic Bax to anti-apoptotic Bcl-2. Taken together, the results indicate that the U-2OS cell growth inhibitory activity of MW was due to mitochondrial-mediated apoptosis, which may partly explain the anticancer activity of millimeter wave treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/22246399', 'no', 'no', 'NA', 5),
(22248279, 'Wu J, Wu X, Lian K, Lin B, Guo L, Ding Z', 'Overexpression of potassium channel ether à go-go in human osteosarcoma.', 'Neoplasma', '2012', 'Overexpression of potassium channel ether à go-go in human osteosarcoma. Human ether à go-go (hEAG) potassium channels are primarily expressed in brain but also frequently overexpressed in solid tumors, which could indicate their potential value for cancer diagnosis and therapy. hEAG1, one member of the hEAG subfamily, has been shown to play a role in neoplastic process. Here we report the expression of hEAG1 in human osteosarcoma detected by a new polyclonal antibody. The full-length hEAG1 cDNA was cloned from human osteosarcoma cell line MG63 by RT-PCR and expressed in Escherichia coli as His tagged protein. The 6His-hEAG1F protein was purified by nickel agarose and used as the antigen to immunize rabbits following standard protocols. The obtained antiserum could detect hEAG1 exogenously expressed in HEK 293 cells. Furthermore, the polyclonal antibody was used to evaluate hEAG1 expression in 42 human osteosarcoma specimens and 19 osteochondromas specimens by immunohistochemistry. hEAG1 was expressed in 71.4% (30/42) osteosarcoma, and 15.8% (3/19) osteochondromas. Moreover, statistical analysis revealed that hEAG1 expression was not dependent on age, sex, site, histology, grade and type in the osteosarcoma specimens. Our data provide evidence that hEAG1 is overexpressed in human osteosarcoma and the hEAG1 polyclonal antibody offers a good tool for further characterization of the oncogenic function of hEAG1 in osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22248279', 'yes', 'no', 'NA', 1),
(22263786, 'Liang C, Li H, Shen C, Lai J, Shi Z, Liu B, Tao HM', 'Genistein potentiates the anti-cancer effects of gemcitabine in human osteosarcoma via the downregulation of Akt and nuclear factor-κB pathway.', 'Anticancer Agents Med Chem', '2012', 'Genistein potentiates the anti-cancer effects of gemcitabine in human osteosarcoma via the downregulation of Akt and nuclear factor-κB pathway. Genistein, a nontoxic flavonoid compound, has potent antitumor activity in various cancer cells. In the present study, we investigated whether genistein could be employed as a novel strategy to enhance the anti-tumor activity of gemcitabine using human osteosarcoma MNNG/HOS tumor model. In vitro, by MTT, electron microscopy, immunobloting and qRT-PCR assay, we found that the combination treatment of genistein and gemcitabine resulted in stronger growth inhibition and apoptosis induction through the downregulation of NF-κB activity and Akt activation in osteosarcoma cells. Moreover, the synergetic effects were observed when genistein was replaced by PI3K/Akt-pathway inhibitor (LY-294002) or NF-κB inhibitor (BAY11-7082). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-κB activity and Akt activation in xenografts. Taken together, these results provide in vitro and in vivo evidence that genistein abrogates gemcitabine-induced activation of NF-κB and increases the chemosensitization of osteosarcoma to gemcitabine. Combination therapy appears as a rational and novel approach for osteosarcoma treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/22263786', 'no', 'no', 'genistein|gemcitabine|LY-294002|BAY11-7082', 2),
(22274866, 'Qu JT, Wang M, He HL, Tang Y, Ye XJ', 'The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: a meta-analysis and systemic review.', 'J Cancer Res Clin Oncol', '2012', 'The prognostic value of elevated vascular endothelial growth factor in patients with osteosarcoma: a meta-analysis and systemic review. Osteosarcoma is a primary malignancy of bone. Although new therapies continue to emerge, osteosarcoma-related morbidity and mortality remain high. Various studies have evaluated the prognostic value of VEGF levels in osteosarcoma patients, but they have yielded conflicting results.The 5-year survival of each study was aggregated following a methodological assessment, and a systematic review of eligible studies with meta-analysis and univariate analysis was performed to quantitatively review the correlation of VEGF overexpression with 5-year survival in patients with osteosarcoma.A total of 387 patients in eleven papers were finally considered to be eligible for inclusion in our analysis. Aggregation of the 6 positive results in Kaplan-Meier curve showed a risk ratio of 2.84 (95% CI: 1.39-5.83, P = 0.004) associated with VEGF-positive conditions in comparison with VEGF-negative conditions, suggesting that there was significant association between VEGF positive and the 5-year mortality. But univariate analysis of eleven studies showed that there was a small inverse but not significant relationship between VEGF expression level and the 5-year survival of osteosarcoma patients, but stage III, neo-chemotherapy, the primary tumor location, osteoblastic histological subtype and the source of patients showed a significant impact on the 5-year survival of patients.The prognostic significance of VEGF expression in all its isoforms is still unknown based on the limited data available, but we find VEGF165 may play an important role. Future studies should examine the relationship between VEGF isoform expression and patients'' survival and the relationship between VEGF isoform expression and EMMPRIN expression, which could be helpful for predicting the prognosis of patients with osteosarcoma. Once the conclusion of whether the VEGF and its isoforms playing a role in osteosarcoma were reached, it would help guide clinical decision-making regarding therapy and outcomes. In addition, we recommend a >25% positive staining of the cells as a VEGF-positive cut-off value in immunohistochemistry, since we find a relatively strict detecting method is likely to yield significant result in the 5-year survival of patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/22274866', 'yes', 'yes', 'NA', 2),
(22286748, 'Shang X, Wang Y, Zhao Q, Wu K, Li X, Ji X, He R, Zhang W', 'siRNAs target sites selection of ezrin and the influence of RNA interference on ezrin expression and biological characters of osteosarcoma cells.', 'Mol Cell Biochem', '2012', 'siRNAs target sites selection of ezrin and the influence of RNA interference on ezrin expression and biological characters of osteosarcoma cells. Ezrin, one of the ezrin/radixin/moesin (ERM) protein family which act as membrane organizers and linkers between plasma membrane and cytoskeleton, has attracted much attention as a crucial factor for tumor metastasis. Overexpression of ezrin has been correlated with the metastatic potential of several cancers especially for osteosarcoma. Short interfering RNA (siRNA) downregulate gene expression through an enzyme-mediated process named RNA interference (RNAi). RNAi has rapidly come to be recognized as a powerful tool for the study of gene function and a potential target therapy. In the present study, the human osteosarcoma cell line MG63 was cultured. Three siRNAs targeting ezrin mRNA were designed by the multiple computational methods and then were sythesized. These siRNAs were transfected into osteosarcoma cells. Then the expression of ezrin mRNA and protein in osteosarcoma cells was detected. The cellular proliferation and apoptosis was evaluated. C726–U730, C1653–A1661 and G1749–A1771 were selected to be the suitable target sites through the multiple computational methods because of their ideal secondary structures and hybridization thermodynamics. siRNAs against G1749–A1771 downregulated the expression level of ezrin mRNA and protein, inhibit the cellular proliferation and promoted the cellular apoptosis effectively. There is a significant correlation between the multiple computational methods and the efficacy of the corresponding siRNAs. siRNAs targeting ezrin may have therapeutic potential as inhibitors of osteosarcoma metastasis.', 'http://www.ncbi.nlm.nih.gov/pubmed/22286748', 'no', 'no', 'NA', 1),
(22292074, 'Both J, Wu T, Bras J, Schaap GR, Baas F, Hulsebos TJ', 'Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma.', 'PLoS One', '2012', 'Identification of novel candidate oncogenes in chromosome region 17p11.2-p12 in human osteosarcoma. Osteosarcoma is the most common primary malignancy of bone. The tumours are characterized by high genomic instability, including the occurrence of multiple regions of amplifications and deletions. Chromosome region 17p11.2-p12 is amplified in about 25% of cases. In previous studies, COPS3 and PMP22 have been identified as candidate oncogenes in this region. Considering the complexity and variation of the amplification profiles for this segment, the involvement of additional causative oncogenes is to be expected. The aim of the present investigation is to identify novel candidate oncogenes in 17p11.2-p12. We selected 26 of in total 85 osteosarcoma samples (31%) with amplification events in 17p11.2-p12, using quantitative PCR for 8 marker genes. These were subjected to high-resolution SNP array analysis and subsequent GISTIC analysis to identify the most significantly amplified regions. Two major amplification peaks were found in the 17p11.2-p12 region. Overexpression as a consequence of gene amplification is a major mechanism for oncogene activation in tumours. Therefore, to identify the causative oncogenes, we next determined expression levels of all genes within the two segments using expression array data that could be generated for 20 of the selected samples. We identified 11 genes that were overexpressed through amplification in at least 50% of cases. Nine of these, c17orf39, RICH2, c17orf45, TOP3A, COPS3, SHMT1, PRPSAP2, PMP22, and RASD1, demonstrated a significant association between copy number and expression level. We conclude that these genes, including COPS3 and PMP22, are candidate oncogenes in 17p11.2-p12 of importance in osteosarcoma tumourigenesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/22292074', 'yes', 'no', 'NA', 9),
(22292654, 'Zhang G, Li M, Jin J, Bai Y, Yang C', 'Knockdown of S100A4 decreases tumorigenesis and metastasis in osteosarcoma cells by repression of matrix metalloproteinase-9.', 'Asian Pac J Cancer Prev', '2011', 'Knockdown of S100A4 decreases tumorigenesis and metastasis in osteosarcoma cells by repression of matrix metalloproteinase-9. Osteosarcoma (OS), the most frequent bone tumor in children and adolescents, is highly malignant. Metastases are the major cause of death, and patients with relapse have a poor prognosis. Given the associations of S100A4 with OS and tumor metastasis, we explored its potential roles in OS metastasis. Among 32 OS (16 metastatic and 16 non- metastatic) specimens examined, we found a significant increase of S100A4 mRNA in metastatic tissues, and more importantly, expression of S100A4 and MMP-9 to be strongly correlated in patients who had lymph node or distant metastasis. We observed that siRNA mediated suppression of the S100A4 gene significantly reduced the proliferative and invasive capability of highly invasive OS cells, with a reduced rate of tumor growth and metastasis under in vivo conditions. Matrix metalloproteinase 9 (MMP-9) proved highly responsive to S100A4 gene suppression, demonstrating significant reduction in proteolytic activity, while overexpression of S100A4 increased the expression and proteolytic activity of MMP-9. Links of S100A4 with cell motility were confirmed by depletion which resulted in reduced cell migration. Moreover, loss of cell metastatic potential was completely rescued by overexpression of MMP-9. Collectively, our findings indicate that S100A4 contributes to OS metastasis by stimulating MMP-9 expression, suggesting potential as a novel diagnostic biomarker for OS progression as well as a therapeutic target.', 'http://www.ncbi.nlm.nih.gov/pubmed/22292654', 'yes', 'yes', 'NA', 2),
(22297550, 'Folio C, Zalacain M, Zandueta C, Ormazábal C, Sierrasesúmaga L, San Julián M, de las Rivas J, Toledo G, Lecanda F, Patiño-García A', 'Cortactin (CTTN) overexpression in osteosarcoma correlates with advanced stage and reduced survival.', 'Cancer Biomark', 'NA', 'Cortactin (CTTN) overexpression in osteosarcoma correlates with advanced stage and reduced survival. The cortactin (CTTN) gene has been found, by transcriptomic profiling, to be overexpressed in pediatric osteosarcoma. The location of CTTN at 11q13 and the role of cortactin in cytoskeleton restructuring make CTTN of interest as a potential biomarker for osteosarcoma.Osteoblasts were isolated from 20 high-grade osteosarcomas before chemotherapy, and paired with cell samples from normal tissue, prior to RNA expression analysis on HG-U133A chips (Affymetrix). Semiquantitative CTTN mRNA expression was analyzed by real-time PCR. An osteosarcoma tissue microarray (TMA) containing 233 tissue spots from 48 patients was used for an immunohistochemical (IHC) study of cortactin.Transcriptomic profiling and real-time PCR analysis indicated increased CTTN expression in osteosarcomas (p = 0.001, Student''s T test). TMA IHC showed cortactin to be present more frequently and in greater abundance in osteosarcomas than non-tumoral osteoblastic samples (p< 0.006, Mann-Withney test). Analysis of clinical outcomes indicated that overall survival for patients with primary tumors positive for cortactin was significantly lower than that for patients with cortactin negative (or only weakly staining) tumors (p = 0.0278, Log-rank test).Our preliminary data support the hypothesis that over-expression of cortactin, contained in the 11q13 amplicon, is involved in osteosarcoma carcinogenesis. The potential of cortactin overexpression as a biomarker for osteosarcoma is consolidated.', 'http://www.ncbi.nlm.nih.gov/pubmed/22297550', 'yes', 'no', 'NA', 1),
(22301501, 'Yoshida A, Ushiku T, Motoi T, Beppu Y, Fukayama M, Tsuda H, Shibata T', 'MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype.', 'Am J Surg Pathol', '2012', 'MDM2 and CDK4 immunohistochemical coexpression in high-grade osteosarcoma: correlation with a dedifferentiated subtype. Low-grade osteosarcomas comprise a distinct subset of osteosarcomas. They may occasionally dedifferentiate into high-grade tumors, typically in the form of high-grade osteosarcoma, which are histologically indistinguishable from conventional osteosarcomas. MDM2 and CDK4 are often amplified in low-grade osteosarcomas and their dedifferentiated counterparts, and the encoded proteins are accordingly overexpressed. As MDM2/CDK4 expression was reportedly rare in conventional osteosarcoma, we hypothesized that these markers may help separate dedifferentiated osteosarcoma from the conventional type. To test this, we performed MDM2 and CDK4 immunohistochemistry on 81 primary and 26 recurrent/metastatic high-grade osteosarcomas and correlated these data with the histology of the primary resection material, with particular attention to the potential presence of any coexisting low-grade osteosarcomatous components. MDM2 and CDK4 coexpression was identified in 7 cases, and on careful histologic review 6 of them were discovered to contain foci of coexisting low-grade elements. One case was a known dedifferentiated parosteal osteosarcoma, and the remaining 5 cases were newly identified dedifferentiated osteosarcomas in which the limited low-grade components were originally unrecognized. An additional 11 cases expressed either marker alone, whereas the remaining 89 cases were negative for both markers; no resection material from these 100 cases presented with a low-grade component. MDM2/CDK4 gene amplification status, determined by quantitative polymerase chain reaction in selected cases, was largely concordant with immunoexpression. Our data suggest that MDM2 and CDK4 coexpression in high-grade osteosarcomas is sensitive and specific to those that progressed from low-grade osteosarcomas, and immunohistochemistry may help identify this dedifferentiated subgroup to facilitate accurate subclassification.', 'http://www.ncbi.nlm.nih.gov/pubmed/22301501', 'yes', 'yes', 'NA', 2),
(22301993, 'Huang J, Liu K, Yu Y, Xie M, Kang R, Vernon P, Cao L, Tang D, Ni J', 'Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma.', 'Autophagy', '2012', 'Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma. Autophagy is a catabolic process critical to maintaining cellular homeostasis and responding to cytotoxic insult. Autophagy is recognized as \\programmed cell survival\\ in contrast to apoptosis or programmed cell death. Upregulation of autophagy has been observed in many types of cancers and has been demonstrated to both promote and inhibit antitumor drug resistance depending to a large extent on the nature and duration of the treatment-induced metabolic stress as well as the tumor type. Cisplatin, doxorubicin and methotrexate are commonly used anticancer drugs in osteosarcoma, the most common form of childhood and adolescent cancer. Our recent study demonstrated that high mobility group box 1 protein (HMGB1)-mediated autophagy is a significant contributor to drug resistance in osteosarcoma cells. Inhibition of both HMGB1 and autophagy increase the drug sensitivity of osteosarcoma cells in vivo and in vitro. Furthermore, we demonstrated that the ULK1-FIP200 complex is required for the interaction between HMGB1 and BECN1, which then promotes BECN1-PtdIns3KC3 complex formation during autophagy. Thus, these findings provide a novel mechanism of osteosarcoma resistance to therapy facilitated by HMGB1-mediated autophagy and provide a new target for the control of drug-resistant osteosarcoma patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/22301993', 'no', 'no', 'doxorubicin|cisplatin|methotrexate', 4),
(22333159, 'Han J, Yong B, Luo C, Tan P, Peng T, Shen J', 'High serum alkaline phosphatase cooperating with MMP-9 predicts metastasis and poor prognosis in patients with primary osteosarcoma in Southern China.', 'World J Surg Oncol', '2012', 'High serum alkaline phosphatase cooperating with MMP-9 predicts metastasis and poor prognosis in patients with primary osteosarcoma in Southern China. Osteosarcoma is a malignant tumor with high ability to form invasion and metastasis. Identifying prognostic factor in osteosarcoma is helpful to select those patients for more aggressive management. Our study evaluated serum alkaline phosphatase (ALP) cooperating with matrix metalloproteinase-9 (MMP-9) as an important prognostic predictor for local recurrence and distant metastasis of osteosarcoma.177 cases were included from the osteosarcoma patients treated at 1st Affiliated Hospital of Sun Yat-sen University (1999-2008). Pre-chemotherapy serum ALP (pre-ALP) were studied and correlated with tumor recurrence, lung metastasis and patient survival. MMP-9 protein in tumor tissues was detected by immunohistochemistry and correlated with pre-ALP level.Pre-ALP were partitioned into normal, high, and very high groups, in each group the incidence of metastases was 12.2%, 21.2% and 34.6%, respectively (p = 0.007). In the three groups the mean disease-free survival (DFS) was 57 ± 3.15, 28 ± 3.57 and 14 ± 3.35 months, respectively (p < 0.001); overall survival (OS) was 92 ± 26.89, 39 ± 8.61 and 17 ± 5.07 months, respectively (p < 0.001). By multivariate analysis, elevated serum pre-ALP were associated with shorter DFS (p = 0.018) and OS (p = 0.031). If elevated ALP levels decreased after clinical treatment, the incidence of lung metastasis rate decreased (p = 0.028); DFS and OS were both prolonged (p < 0.001). Pre-ALP was also positively correlated with MMP-9 expression (p = 0.015) in tumor tissue.Pre-ALP was an independent prognostic factor for the survival of osteosarcoma patients in south China, and correlated with MMP-9 expression and lung metastasis. ALP can also serve as a prognostic marker for treatment, and merit large-scale validation studies.', 'http://www.ncbi.nlm.nih.gov/pubmed/22333159', 'yes', 'yes', 'NA', 2);
INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(22338054, 'Nunez AL, Siegal GP, Reddy VV, Wei S', 'CD138 (syndecan-1) expression in bone-forming tumors.', 'Am J Clin Pathol', '2012', 'CD138 (syndecan-1) expression in bone-forming tumors. CD138 (syndecan-1), a cell surface proteoglycan, is sensitive and specific for plasmacytic differentiation in hematologic disorders. Expression of CD138 has been observed in a majority of epithelial neoplasms and, rarely, soft tissue tumors. However, its expression in bone tumors has not been evaluated. We studied CD138 expression in 27 osteosarcomas, 12 benign bone-forming tumors (osteoid osteoma and osteoblastoma), and 17 reactive bone cases. CD138 expression was also evaluated in a tissue microarray (TMA) constructed from 24 osteosarcomas, 24 chondrosarcomas, 12 giant cell tumors of bone, and 9 normal bone samples. Membranous expression of CD138 was found in an average of 31% of osteosarcoma cases (16/51; 14/27 [52%] in in-house cases; 2/24 [8%] in TMA cases) and in 83% of osteoid osteoma/osteoblastoma cases (10/12). Subsequent immunoglobulin κ and λ stains were negative in the CD138+ cases. All cases of chondrosarcoma, giant cell tumor of bone, and normal/reactive bone tested were nonreactive with anti-CD138. Our results show that CD138 reactivity for neoplastic cells in bone is not a definitive marker for plasmacytic origin, and caution is required to interpret CD138+ cells from a bony lesion for which a hematologic etiology has not been established.', 'http://www.ncbi.nlm.nih.gov/pubmed/22338054', 'yes', 'no', 'NA', 1),
(22340557, 'Jin S, Shen JN, Peng JQ, Wang J, Huang G, Li MT', 'Increased expression of serum gelsolin in patients with osteosarcoma.', 'Chin Med J (Engl)', '2012', 'Increased expression of serum gelsolin in patients with osteosarcoma. Identification of potential serum biomarkers of osteosarcoma to aid in its early diagnosis and in the discovery of possible therapeutic targets is an area of increasing interest.Two-dimensional difference-in-gel electrophoresis was used to assess multiple serum samples in patients with osteosarcoma. In addition, differential expression of protein biomarkers was characterized in osteosarcoma serum by using matrix-assisted desorption/ionization time-of-flight mass spectrometry coupled with database interrogation. Serum samples from four individuals with osteosarcoma and four age- and sex-matched healthy control subjects were compared.Fifty-eight significant protein spot features in the osteosarcoma sera were found. These spot features were excised, digested with trypsin, and analyzed with mass spectrometry. Gelsolin was down-regulated only in osteosarcoma. Furthermore, Western blotting and enzyme linked immunosorbent assay (ELISA) confirmed decreased levels of gelsolin in the osteosarcoma serum samples.These results indicated that gelsolin might have great potential as a biomarker of osteosarcoma and as a potential target for gene therapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/22340557', 'yes', 'yes', 'NA', 1),
(22344865, 'Zambo I, Hermanova M, Adamkova Krakorova D, Mudry P, Zitterbart K, Kyr M, Vesely K, Sterba J, Veselska R', 'Nestin expression in high-grade osteosarcomas and its clinical significance.', 'Oncol Rep', '2012', 'Nestin expression in high-grade osteosarcomas and its clinical significance. Nestin has been detected in various malignancies and its expression correlates with advanced grade in some neoplasms. The aim of this study was to examine nestin expression in high-grade osteosarcomas and to determine its prognostic value. Using immunohistochemistry and immunofluorescence, we evaluated nestin expression in tumor tissue samples from 45 patients with high-grade osteosarcomas. In both methods, the frequency of nestin-positive tumor cells was classified into three categories (1+, 2+ and 3+ for immunohistochemistry; 1F+, 2F+ and 3F+ for immunofluorescence) and clinicopathological correlations were statistically evaluated and analyzed. Nestin-positive tumor cells were detected in all of the examined osteosarcomas using both immunohistochemistry and immunofluorescence, although the proportion of undoubtedly positive neoplastic cells varied in individual samples from a few nestin-positive tumor cells to diffuse nestin positivity. High levels of nestin expression detected by immunofluorescence (2F+ and 3F+) were associated with worse clinical outcomes (OS, p=0.031; EFS, p<0.001). However, high levels of nestin expression as measured by immunohistochemistry trended towards shorter patient survival rates but did not reach statistical significance. Despite significantly shorter survival rates observed in patients with high levels of nestin expression assessed by immunofluorescence, nestin does not seem to represent a powerful prognostic marker that would be superior to conventional methods.', 'http://www.ncbi.nlm.nih.gov/pubmed/22344865', 'yes', 'no', 'NA', 1),
(22350417, 'Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL, Volinia S, Stein GS, Croce CM, Lian JB, Aqeilan RI', 'miRNA signatures associate with pathogenesis and progression of osteosarcoma.', 'Cancer Res', '2012', 'miRNA signatures associate with pathogenesis and progression of osteosarcoma. Osteosarcoma remains a leading cause of cancer death in adolescents. Treatment paradigms and survival rates have not improved in two decades. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. Here we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a,miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p. We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish a miRNA signature associated with pathogenesis of osteosarcoma as well as critical pre-treatment biomarkers of metastasis and responsiveness to therapy.©2012 AACR.', 'http://www.ncbi.nlm.nih.gov/pubmed/22350417', 'yes', 'no', 'NA', 10),
(22354724, 'Li C, Chunbao L, Cheng Q, Qianpeng C, Liu J, Jia L, Wang B, Bin W, Chen D, Dongfeng C, Liu Y, Yujie L', 'Potent growth-inhibitory effect of TRAIL therapy mediated by double-regulated oncolytic adenovirus on osteosarcoma.', 'Mol Cell Biochem', '2012', 'Potent growth-inhibitory effect of TRAIL therapy mediated by double-regulated oncolytic adenovirus on osteosarcoma. Osteosarcoma (OS) severely threatens the health of young people and understanding on the molecular mechanisms of OS etiology enables gene therapy to become an effective therapeutic modality. However, insufficient expression level of genes using existing vectors limits the clinical application of gene therapy for OS. To solve the problem, we developed an oncolytic adenoviral vector, OAT, which can selectively and efficiently replicate in OS cells to enhance the expression of transferred genes. We demonstrated that OAT-mediated TRAIL expression is significantly elevated after infection of OS cells than replication-incompetent Ad5 vector. Increased antitumor capacity was observed in OS cells after OAT-TRAIL treatment both in vitro and in vivo. In normal cells, adenoviral replication, TRAIL expression and growth-inhibiting effect were quite limited when OAT-TRAIL was administrated, showing a high biosafety of this oncolytic adenoviral vector. Collectively, we generated an efficient and promising expression vector for OS gene therapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/22354724', 'no', 'no', 'NA', 1),
(22371553, 'Masrouha KZ, Khattab R, Tawil A, Abdallah A, Saghieh S, Haidar R, Abboud M, Khoury NJ', 'A preliminary investigation of Beta-hCG expression in patients with osteosarcoma.', 'J Bone Joint Surg Br', '2012', 'A preliminary investigation of Beta-hCG expression in patients with osteosarcoma. There are eight reported cases in the literature of osteosarcomas secreting β-hCG. Our primary aim was to investigate the rate of β-hCG expression in osteosarcoma and attempt to understand the characteristics of osteosarcomas that secrete β-hCG. We reviewed 37 histopathology slides (14 biopsies and 23 surgical specimens) from 32 patients with osteosarcoma. The slides were retrospectively stained for β-hCG expression. Patient and tumour characteristics, including age, gender, tumour location, subtype, proportion of necrosis, presence of metastases and recurrence were recorded. A total of five of the 32 tumours were found to be positive for β-hCG expression (one strongly and four weakly). This incidence of this expression was found in tumours with poor histological response to neoadjuvant chemotherapy. The use of β-hCG expression as a diagnostic, prognostic or follow-up marker is questionable and needs further investigation with a larger sample size.', 'http://www.ncbi.nlm.nih.gov/pubmed/22371553', 'yes', 'yes', 'NA', 1),
(22382389, 'Castro-Gamero AM, Borges KS, da Silva Silveira V, Lira RC, de Paula Gomes Queiroz R, Valera FC, Scrideli CA, Umezawa K, Tone LG', 'Inhibition of nuclear factor-κB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells.', 'Anticancer Drugs', '2012', 'Inhibition of nuclear factor-κB by dehydroxymethylepoxyquinomicin induces schedule-dependent chemosensitivity to anticancer drugs and enhances chemoinduced apoptosis in osteosarcoma cells. Osteosarcoma (OS) is the most common primary malignant bone tumor, usually developing in children and adolescents, and is highly invasive and metastatic, potentially developing chemoresistance. Thus, novel effective treatment regimens are urgently needed. This study was the first to investigate the anticancer effects of dehydroxymethylepoxyquinomicin (DHMEQ), a highly specific nuclear factor-κB (NF-κB) inhibitor, on the OS cell lines HOS and MG-63. We demonstrate that NF-κB blockade by DHMEQ inhibits proliferation, decreases the mitotic index, and triggers apoptosis of OS cells. We examined the effects of combination treatment with DHMEQ and cisplatin, doxorubicin, or methotrexate, drugs commonly used in OS treatment. Using the median effect method of Chou and Talalay, we evaluated the combination indices for simultaneous and sequential treatment schedules. In all cases, combination with a chemotherapeutic drug produced a synergistic effect, even at low single-agent cytotoxic levels. When cells were treated with DHMEQ and cisplatin, a more synergistic effect was obtained using simultaneous treatment. For the doxorubicin and methotrexate combination, a more synergistic effect was achieved with sequential treatment using DHMEQ before chemotherapy. These synergistic effects were accompanied by enhancement of chemoinduced apoptosis. Interestingly, the highest apoptotic effect was reached with sequential exposure in both cell lines, independent of the chemotherapeutic agent used. Likewise, DHMEQ decreased cell invasion and migration, crucial steps for tumor progression. Our data suggest that combining DHMEQ with chemotherapeutic drugs might be useful for planning new therapeutic strategies for OS treatment, mainly in resistant and metastatic cases.', 'http://www.ncbi.nlm.nih.gov/pubmed/22382389', 'no', 'no', 'dehydroxymethylepoxyquinomicin', 1),
(22387266, 'Liao CL, Lai KC, Huang AC, Yang JS, Lin JJ, Wu SH, Gibson Wood W, Lin JG, Chung JG', 'Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways.', 'Food Chem Toxicol', '2012', 'Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways. Advanced cancer is a multifactorial disease which complicates treatment if the cancer cells have metastasized calling for the targeting of multiple cellular pathways. Gallic acid (GA) is known to possess multiple pharmacological activity including antitumor effects. This study investigated the mechanisms for the anticancer properties of GA on migration and invasion of human osteosarcoma U-2 OS cells. The migration and invasion in U-2 OS cells were determined by a Boyden chamber transwell assay. The expression levels and activities of MMP-2 and MMP-9 were measured by Western blotting, real-time PCR and gelatin zymography assays. All examined proteins levels from Western blotting indicated that GA decreased the protein levels of GRB2, PI3K, AKT/PKB, PKC, p38, ERK1/2, JNK, NF-κB p65 in U-2 OS cells. GA also inhibited the activities of AKT, IKK and PKC by in vitro kinase assay. GA suppressed the migration and invasive ability of U-2 OS cells, and it decreased MMP-2 and MMP-9 protein and mRNA levels and secreted enzyme activities in vitro. These results suggest that potential signaling pathways of GA-inhibited migration and invasion in U-2 OS cells may be due to down-regulation of PKC, inhibition of mitogen-activated protein kinase (MAPK) and PI3K/AKT, resulting in inhibition of MMP-2 and MMP-9 expressions.Copyright © 2012 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22387266', 'no', 'no', 'gallic acid', 11),
(22390926, 'Cheng WH, Wu RT, Wu M, Rocourt CR, Carrillo JA, Song J, Bohr CT, Tzeng TJ', 'Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death.', 'Biochem Biophys Res Commun', '2012', 'Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death. Mutations in the Werner syndrome protein (WRN), a caretaker of the genome, result in Werner syndrome, which is characterized by premature aging phenotypes and cancer predisposition. Methylseleninic acid (MSeA) can activate DNA damage responses and is a superior compound to suppress tumorigenesis in mouse models of cancer. To test the hypothesis that targeting WRN can potentiate selenium toxicity in cancer cells, isogenic WRN small hairpin RNA (shRNA) and control shRNA U-2 OS osteosarcoma cells were treated with MSeA for 2d, followed by recovery for up to 7d. WRN deficiency sensitized U-2 OS cells to MSeA-induced necrotic death. Co-treatment with the ataxia-telangiectasia mutated (ATM) kinase inhibitor KU55933 desensitized the control shRNA cells, but not WRN shRNA cells, to MSeA treatment. WRN did not affect MSeA-induced ATM phosphorylation on Ser-1981 or H2A.X phosphorylation on Ser-139, but promoted recovery from the MSeA-induced DNA damage. Taken together, WRN protects U-2 OS osteosarcoma cells against MSeA-induced cytotoxicity, suggesting that oxidative DNA repair pathway is a promising target for improving the efficacy of selenium on tumor suppression.Copyright © 2012 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22390926', 'no', 'no', 'Methylseleninic acid|KU55933', 1),
(22390931, 'Tan P, Zou C, Yong B, Han J, Zhang L, Su Q, Yin J, Wang J, Huang G, Peng T, Shen J', 'Expression and prognostic relevance of PRAME in primary osteosarcoma.', 'Biochem Biophys Res Commun', '2012', 'Expression and prognostic relevance of PRAME in primary osteosarcoma. The preferentially expressed antigen of melanoma (PRAME), a cancer-testis antigen with unknown function, is expressed in many human malignancies and is considered an attractive potential target for tumor immunotherapy. However, studies of its expression and function in osteosarcoma have rarely been reported. In this study, we found that PRAME is expressed in five osteosarcoma cell lines and in more than 70% of osteosarcoma patient specimens. In addition, an immunohistochemical analysis showed that high PRAME expression was associated with poor prognosis and lung metastasis. Furthermore, PRAME siRNA knockdown significantly suppressed the proliferation, colony formation, and G1 cell cycle arrest in U-2OS cells. Our results suggest that PRAME plays an important role in cell proliferation and disease progression in osteosarcoma. However, the detail mechanisms of PRAME function in osteosarcoma require further investigation.Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22390931', 'yes', 'yes', 'NA', 1),
(22422053, 'Oveland E, Wergeland L, Hovland R, Lorens JB, Gjertsen BT, Fladmark KE', 'Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines.', 'Cell Biol Toxicol', '2012', 'Ectopic expression of Flt3 kinase inhibits proliferation and promotes cell death in different human cancer cell lines. Stable ectopic expression of Flt3 receptor tyrosine kinase is usually performed in interleukin 3 (IL-3)-dependent murine cell lines like Ba/F3, resulting in loss of IL-3 dependence. Such high-level Flt3 expression has to date not been reported in human acute myeloid leukemia (AML) cell lines, despite the fact that oncogenic Flt3 aberrancies are frequent in AML patients. We show here that ectopic Flt3 expression in different human cancer cell lines might reduce proliferation and induce apoptotic cell death, involving Bax/Bcl2 modulation. Selective depletion of Flt3-expressing cells occurred in human AML cell lines transduced with retroviral Flt3 constructs, shown here using the HL-60 leukemic cell line. Flt3 expression was investigated in two cellular model systems, the SAOS-2 osteosarcoma cell line and the human embryonic kidney HEK293 cell line, and proliferation was reduced in both systems. HEK293 cells underwent apoptosis upon ectopic Flt3 expression and cell death could be rescued by overexpression of Bcl-2. Furthermore, we observed that the Flt3-induced inhibition of proliferation in HL-60 cells appeared to be Bax-dependent. Our results thus suggest that excessive Flt3 expression has growth-suppressive properties in several human cancer cell lines.', 'http://www.ncbi.nlm.nih.gov/pubmed/22422053', 'no', 'no', 'NA', 2),
(22426824, 'Onishi Y, Kawamoto T, Kishimoto K, Hara H, Fukase N, Toda M, Harada R, Kurosaka M, Akisue T', 'PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma.', 'Int J Oncol', '2012', 'PKD1 negatively regulates cell invasion, migration and proliferation ability of human osteosarcoma. Osteosarcoma (OS) is a primary malignancy of the bone, with a tendency to metastasize early. Despite intensive chemotherapy and surgical resection, more than 30% of patients develop distant metastases, and the prognosis of patients with metastases is essentially poor. Members of the protein kinase D (PKD) family are serine/threonine kinases, and have been studied in various cancers. Among the three different isoforms of this family, PKD1 is one of the best understood for its role in human malignancies; however, its role in musculoskeletal tumors has not been studied. In the present study, we investigated the role of PKD1 in human OS. We first analyzed PKD1 mRNA expression in human musculoskeletal tumor tissue samples by quantitative real-time PCR. PKD1 expression in OS samples was significantly lower than that in benign schwannoma samples, and this was correlated with metastatic potential. In in vitro studies, overexpression of PKD1 by plasmid transfection decreased OS cell invasion, migration and proliferation, and significantly decreased matrix metalloproteinase (MMP)2 mRNA expression. Conversely, siRNA knockdown of PKD1 increased invasion, migration and proliferation of OS cells, and MMP2 expression was markedly increased. Furthermore, overexpression of PKD1 significantly reduced in vivo tumor growth of OS cells. These results demonstrated that low expression of PKD1 may contribute to increased cell invasion, migration and proliferation ability of human OS. Taken together, our findings strongly suggest that PKD1 may negatively regulate the malignant potential of human OS, and may be a therapeutic target for human OS in the clinical setting.', 'http://www.ncbi.nlm.nih.gov/pubmed/22426824', 'yes', 'yes', 'NA', 2),
(22446894, 'Li Y, Liao Q, Li K, Zhong D, Weng X, Mi M', 'Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model.', 'Mol Med Rep', '2012', 'Knockdown of endothelin A receptor expression inhibits osteosarcoma pulmonary metastasis in an orthotopic xenograft mouse model. Previous in vitro studies suggest that the endothelin A receptor (ETAR) could be a potential therapeutic target for osteosarcoma (OS) metastasis. In the present study, we assessed for the first time the role of ETAR in OS proliferation and pulmonary metastasis in vivo. MG-63 human OS cells were stably transduced with ETAR shRNA or scramble control shRNA and injected into the tibia of nude mice to generate an orthotopic xenograft OS model. The mice were divided into three groups (n=10 each group): i) the untransduced control group, where the mice were injected with untransduced MG-63 cells; ii) the scramble control group, where the mice were injected with cells stably transduced with the scramble control shRNA; iii) the ETAR-shRNA group, where the mice were injected with cells stably transduced with ETAR shRNA. The ETAR shRNA knocked down more than 75% of endogenous ETAR expression and significantly inhibited invasion, but not proliferation/viability of MG-63 cells in vitro. In the orthotopic xenograft OS mouse model, no significant difference in the tumor volume was observed over time among the untransduced control, the scramble control and the ETAR-shRNA groups. However, a combination of clinical signs, organ examinations and quantitative clonogenic lung metastasis assays showed that lung metastasis in the ETAR-shRNA group was significantly lower than that in the control groups. Immunohistochemical analyses revealed that the matrix metalloproteinase-2 (MMP-2) expression was significantly reduced in the ETAR-shRNA group compared with the control groups. The results were confirmed with western blot analyses using primary tumor tissues or the stably transduced MG-63 cells. In conclusion, we demonstrated in an orthotopic xenograft OS model that ETAR is critical for OS pulmonary metastasis, but not for tumor growth. This study provides the first in vivo evidence suggesting an important role for ETAR in OS pulmonary metastasis.', 'http://www.ncbi.nlm.nih.gov/pubmed/22446894', 'no', 'no', 'NA', 2),
(22454324, 'Kuijjer ML, Rydbeck H, Kresse SH, Buddingh EP, Lid AB, Roelofs H, Bürger H, Myklebost O, Hogendoorn PC, Meza-Zepeda LA, Cleton-Jansen AM', 'Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data.', 'Genes Chromosomes Cancer', '2012', 'Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data. High-grade osteosarcoma is a tumor with a complex genomic profile, occurring primarily in adolescents with a second peak at middle age. The extensive genomic alterations obscure the identification of genes driving tumorigenesis during osteosarcoma development. To identify such driver genes, we integrated DNA copy number profiles (Affymetrix SNP 6.0) of 32 diagnostic biopsies with 84 expression profiles (Illumina Human-6 v2.0) of high-grade osteosarcoma as compared with its putative progenitor cells, i.e., mesenchymal stem cells (n = 12) or osteoblasts (n = 3). In addition, we performed paired analyses between copy number and expression profiles of a subset of 29 patients for which both DNA and mRNA profiles were available. Integrative analyses were performed in Nexus Copy Number software and statistical language R. Paired analyses were performed on all probes detecting significantly differentially expressed genes in corresponding LIMMA analyses. For both nonpaired and paired analyses, copy number aberration frequency was set to >35%. Nonpaired and paired integrative analyses resulted in 45 and 101 genes, respectively, which were present in both analyses using different control sets. Paired analyses detected >90% of all genes found with the corresponding nonpaired analyses. Remarkably, approximately twice as many genes as found in the corresponding nonpaired analyses were detected. Affected genes were intersected with differentially expressed genes in osteosarcoma cell lines, resulting in 31 new osteosarcoma driver genes. Cell division related genes, such as MCM4 and LATS2, were overrepresented and genomic instability was predictive for metastasis-free survival, suggesting that deregulation of the cell cycle is a driver of osteosarcomagenesis.Copyright © 2012 Wiley Periodicals, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/22454324', 'yes', 'no', 'NA', 2),
(22457788, 'Yan K, Gao J, Yang T, Ma Q, Qiu X, Fan Q, Ma B', 'MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo.', 'PLoS One', '2012', 'MicroRNA-34a inhibits the proliferation and metastasis of osteosarcoma cells both in vitro and in vivo. MicroRNAs (miRNAs) are a class of endogenously expressed, small noncoding RNAs, which suppress its target mRNAs at the post-transcriptional level. Studies have demonstrated that miR-34a, which is a direct target of the p53 tumor suppressor gene, functions as a tumor suppressor and is associated with the tumor growth and metastasis of various human malignances. However, the role of miR-34a in osteosarcoma has not been totally elucidated. In the present study, the effects of miR-34a on osteosarcoma and the possible mechanism by which miR-34a affected the tumor growth and metastasis of osteosarcoma were investigated.Over-expression of miR-34a partially inhibited proliferation, migration and invasion of osteosarcoma cells in vitro, as well as the tumor growth and pulmonary metastasis of osteosarcoma cells in vivo. c-Met is a target of miR-34a, and regulates the migration and invasion of osteosarcoma cells. Osteosarcoma cells over-expressing miR-34a exhibited a significant decrease in the expression levels of c-Met mRNA and protein simultaneously. Finally, the results from bioinformatics analysis demonstrated that there were multiple putative targets of miR-34a that may be associated with the proliferation and metastasis of osteosarcoma, including factors in Wnt and Notch signaling pathways.The results presented in this study demonstrated that over-expression of miR-34a could inhibit the tumor growth and metastasis of osteosarcoma probably through down regulating c-Met. And there are other putative miR-34a target genes beside c-Met which could potentially be key players in the development of osteosarcoma. Since pulmonary metastases are responsible for mortality of patient carrying osteosarcoma, miR-34a may prove to be a promising gene therapeutic agent. It will be interesting to further investigate the mechanism by which miR-34a functions as a tumor suppressor gene in osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22457788', 'no', 'no', 'NA', 2),
(22471458, 'Wang FS, Chen H, Wu ZY, Lin JH', 'KISS1 expression in osteosarcoma: high in chinese clinical cases, but lower in cell lines.', 'Asian Pac J Cancer Prev', '2011', 'KISS1 expression in osteosarcoma: high in chinese clinical cases, but lower in cell lines. Osteosarcoma is the most common primary bone malignancy with a notorious feature of high metastasis. KISS1 has been identified as a putative human metastasis suppressor gene in numerous types of cancer. This study was aimed to evaluate the relationship between expression of KISS1 and invasion ability in osteosarcoma cell lines, and the relationships between KISS1 expression levels and prognosis of clinical cases.Expression levels of KISS1 in 3 types of osteosarcoma cell lines (MG-63, Saos-2 and U-2 OS) and a normal osteoblast cell line (hF-OB 1.19) were examined using semi-quantitative RT-PCR and immunochemistry staining. Transwell assays were used to detect the cell invasion ability. The osteosarcoma cell lines and specimen sections of osteosarcoma together with control were immuno-stained with KISS1 antibody. The relationship between the clinical data and the expression of KISS1 was evaluated.KISS1 mRNA expression was moderate in U-2 OS, weak in Saos-2 and lost in MG-63. Transwell assays displayed a gradually increased aggressive phenomenon in osteosarcoma cell lines U-2 OS, Saos-2 and MG-63. However, a contrary conclusion was obtained with clinical specimen, a higher positive rate of KISS1 expression being displayed in osteosarcoma patients, especially in metastastic cases, compared to the benign osteochondroma patients. Furthermore, significant earlier distant metastasis was observed in KISS1 positive than negative cases.KISS1 expression levels were found to be decreased with the increasing aggressive ability in osteosarcoma cell lines. However, expression of KISS1 positively correlated with metastasis in osteosarcoma patients.', 'http://www.ncbi.nlm.nih.gov/pubmed/22471458', 'yes', 'yes', 'NA', 1),
(22471480, 'Lu XF, Yang WL, Wan ZH, Li J, Bi ZG', 'Glutathione S-transferase polymorphisms and bone tumor risk in China.', 'Asian Pac J Cancer Prev', '2011', 'Glutathione S-transferase polymorphisms and bone tumor risk in China. We aimed to study the potential role of GSTM1 and GSTT1 in the risk of osteosarcoma in Chinese population.We collected 110 osteosarcomas by pathologic examination and 226 controls from the First Affiliated Hospital of Harbin Medical University during December 2008 to December 2010. Genotyping was based upon duplex polymerase-chain-reaction with the PCR-CTPP method.Individuals carrying null GSTM1 and GSTT1 had 1.50 and 2.07 fold risks of osteosarcoma when compared with non-null genotypes, respectively. The increased risk associated with the GSTT1 polymorphism seemed more evident among males (Null GSTT1 genotype vs. non-null genotype, adjusted OR= 2.43, 95% CI: 1.29-3.30) than females (adjusted OR =1.66, 95% CI: 1.02-2.78). The increased risk was also more evident among individuals aged 15 years or less (adjusted OR for null GSTT1 genotype vs. non-null genotype = 2.24, 95% CI: 1.20-3.24) than those aged more than 15 years (adjusted OR = 1.82, 95% CI: 1.07-2.95).Our study of the association between polymorphisms in GSTM1 and GSTTI and the risk of osteosarcoma in a Chinese population provided evidence that null GSTTI might be a useful marker of susceptibility to osteosarcoma development, especially for male sand young age individuals.', 'http://www.ncbi.nlm.nih.gov/pubmed/22471480', 'yes', 'yes', 'NA', 2),
(22471498, 'Yuan JM, Li XD, Liu ZY, Hou GQ, Kang JH, Huang DY, Du SX', 'Cisplatin induces apoptosis via upregulating Wrap53 in U-2OS osteosarcoma cells.', 'Asian Pac J Cancer Prev', '2011', 'Cisplatin induces apoptosis via upregulating Wrap53 in U-2OS osteosarcoma cells. Wrap531α, a newly identified natural antisense transcript of p53, can regulate p53 expression upon DNA damage. We sought to investigate changes in Wrap53 and p53 levels in an osteosarcoma cell line (U-2OS) exposed to cisplatin and to study apoptosis before and after knockdown of Wrap53. Our RT-PCR analysis showed a dose- dependent 3 to 40-fold increase in Wrap53 mRNA transcript levels in U-2OS exposed to 5 to 20 μM cisplatin. An approximate 2-fold increase was also observed in transcript levels of p53 mRNA. Furthermore, transient knockdown of Wrap53 by siRNAs in U-2OS cells treated with 10 μM cisplatin reduced p53 mRNA transcript levels by up to 50% of those of controls. Immunoblotting analysis showed that in U-2OS cells treated with siRNA against exon 4 of the Wrap53 gene, the protein level of p53 was also markedly reduced. Our findings suggest that cisplatin upregulates the expression of p53 in osteosarcoma cells by upregulating the transcript levels of Wrap53. Finally, measurement of apoptotic cell death by flow cytometry showed that knockdown of Wrap53 reduced apotosis in U-2OS cells induced by cisplatin.', 'http://www.ncbi.nlm.nih.gov/pubmed/22471498', 'no', 'no', 'cisplatin', 2),
(22472569, 'Fan L, Wu Q, Xing X, Wei Y, Shao Z', 'MicroRNA-145 targets vascular endothelial growth factor and inhibits invasion and metastasis of osteosarcoma cells.', 'Acta Biochim Biophys Sin (Shanghai)', '2012', 'MicroRNA-145 targets vascular endothelial growth factor and inhibits invasion and metastasis of osteosarcoma cells. MicroRNAs are important gene regulators that play a profound role in tumorigenesis. MicroRNA-145 (miR-145), an important member in the family of microRNAs, is under-expressed in several types of tumors and acts as a tumor suppressor. The role and probable pathways of miR-145 in osteosarcoma carcinogenesis are still unknown. In this study, we found that miR-145 was significantly under-expressed in osteosarcoma tissues, and the over-expression of miR-145 could inhibit invasion and angiopoiesis of osteosarcoma cells. Furthermore, the results showed that vascular endothelial growth factor (VEGF) expression was down-regulated in osteosarcoma cells after miR-145 transfection. On the basis of these results, we performed the luciferase assay and verified that miR-145 could down-regulate VEGF at the translational level by partially binding to VEGF 3'' untranslated region (3''UTR). Therefore, it can be concluded that miR-145 can inhibit invasion and metastasis of osteosarcoma cells. One of the mechanisms is the down-regulation of VEGF expression by miR-145 by binding to the 3''UTR of VEGF mRNA specifically. These novel findings may have extensive implications for an effective gene therapy of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22472569', 'yes', 'no', 'NA', 2),
(22506069, 'Wang SW, Wu HH, Liu SC, Wang PC, Ou WC, Chou WY, Shen YS, Tang CH', 'CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma.', 'PLoS One', '2012', 'CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma. Osteosarcoma is characterized by a high malignant and metastatic potential. CCL5 (previously called RANTES) was originally recognized as a product of activated T cells, and plays a crucial role in the migration and metastasis of human cancer cells. It has been reported that the effect of CCL5 is mediated via CCR receptors. However, the effect of CCL5 on migration activity and integrin expression in human osteosarcoma cells is mostly unknown.Here we found that CCL5 increased the migration and expression of αvβ3 integrin in human osteosarcoma cells. Stimulation of cells with CCL5 increased CCR5 but not CCR1 and CCR3 expression. CCR5 mAb, inhibitor, and siRNA reduced the CCL5-enhanced the migration and integrin up-regulation of osteosarcoma cells. Activations of MEK, ERK, and NF-κB pathways after CCL5 treatment were demonstrated, and CCL5-induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK, and NF-κB cascades. In addition, over-expression of CCL5 shRNA inhibited the migratory ability and integrin expression in osteosarcoma cells.CCL5 and CCR5 interaction acts through MEK, ERK, which in turn activates NF-κB, resulting in the activations of αvβ3 integrin and contributing the migration of human osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/22506069', 'no', 'no', 'NA', 2),
(22521131, 'Li Y, Zhang J, Ma D, Zhang L, Si M, Yin H, Li J', 'Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling.', 'FEBS J', '2012', 'Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling. The Notch signaling pathway plays critical roles in human cancers, including osteosarcoma, suggesting that the discovery of specific agents targeting Notch would be extremely valuable for osteosarcoma. Curcumin, a naturally occurring phenolic compound found in curcuma longa, has been shown to inhibit proliferation and induce apoptosis of osteosarcoma cells in vitro and tumor growth in xenotransplant or orthotransplant models. However, the precise molecular mechanisms by which curcumin exerts its antitumor activity remain unclear. Here we used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the invasion assay, gene transfection, real-time RT-PCR, western blot and gelatin zymography, to investigate whether the downregulation of Notch-1 contributes to curcumin-induced inhibition of proliferation and invasion in osteosarcoma cells. The results showed that curcumin caused marked inhibition of osteosarcoma cell growth and G2/M phase cell cycle arrest. This was associated with concomitant attenuation of Notch-1 and downregulation of its downstream genes, such as matrix metalloproteinases, resulting in the inhibition of osteosarcoma cell invasion through Matrigel. We also found that specific downregulation of Notch-1 via small-interfering RNA prior to curcumin treatment resulted in enhanced inhibition of cell growth and invasion. These results suggest that antitumor activity of curcumin is mediated through a novel mechanism involving inactivation of the Notch-1 signaling pathway. Our data provide the first evidence that the downregulation of Notch-1 by curcumin may be an effective approach for the treatment of osteosarcoma.© 2012 The Authors Journal compilation © 2012 FEBS.', 'http://www.ncbi.nlm.nih.gov/pubmed/22521131', 'no', 'no', 'curcumin', 1),
(22525461, 'Zhu J, Feng Y, Ke Z, Yang Z, Zhou J, Huang X, Wang L', 'Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin.', 'Am J Pathol', '2012', 'Down-regulation of miR-183 promotes migration and invasion of osteosarcoma by targeting Ezrin. Recent studies have emphasized causative links between aberrant microRNA expression patterns and cancer progression. miR-183 is dysregulated in certain types of human cancers. The expression pattern, clinical significance, and biological role of miR-183 in osteosarcoma, however, remain largely undefined. In this paired analysis, we found that miR-183 was markedly down-regulated in osteosarcoma cells and tissues compared with matching normal bone tissues using RT-qPCR. Statistical analyses revealed that the expression levels of miR-183 significantly correlated with lung metastasis as well as with local recurrence of osteosarcoma. miR-183 expression was inversely correlated with Ezrin mRNA and protein expression levels in osteosarcoma cells as well as in a subset of primary osteosarcoma. Ectopically expressed miR-183 inhibited migratory and invasive abilities of osteosarcoma cells, whereas knockdown of endogenous miR-183 significantly enhanced these abilities. Using a luciferase reporter carrying the 3''-untranslated region (3''-UTR) of Ezrin, we identified Ezrin as a direct target of miR-183. Moreover, ectopic expression of Ezrin could significantly rescue miR-183-suppressed migration and invasion. Of interest, suppression of Ezrin by miR-183 caused a reduction of phosphorylated p44/42 (p-p44/42). Finally, suppression of Ezrin by RNAi mimicked miR-183 action in the suppression of migration and invasion, which was associated with down-regulation of p-p44/42. Taken together, these results suggest that as a tumor suppressor miRNA, miR-183 plays an important role in the aggressiveness of osteosarcoma.Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22525461', 'yes', 'no', 'NA', 4),
(22531343, 'Na KY, Bacchini P, Bertoni F, Kim YW, Park YK', 'Syndecan-4 and fibronectin in osteosarcoma.', 'Pathology', '2012', 'Syndecan-4 and fibronectin in osteosarcoma. Syndecan-4 (SDC4) and fibronectin (FN), which belong to the cell adhesion molecules, have been reported to correlate with tumour growth and invasion in various carcinomas. We aimed to investigate the prognostic value of these molecules in osteosarcoma.Using immunohistochemistry, we compared the expression of these molecules in high grade osteosarcoma to low grade central osteosarcoma, osteoid osteoma and normal bone. Further, the expression of SDC4 and FN were analysed with prognostic factors of high grade osteosarcoma.In high grade osteosarcoma, SDC4 was expressed in 50 of the 65 samples; of these, 32 of 65 showed strong expression profiles. FN was expressed in 46 of 65 samples, and 29 of 65 had evidence of strong expression of this molecule. SDC4 and FN expression were increased in high grade osteosarcoma as compared to other tissues. Strong SDC4 expression was associated with the occurrence of distant metastasis and a large tumour size, and strong FN expression was associated with the occurrence of distant metastasis. Strong expression of SDC4 or FN was associated with significantly shorter overall survival, respectively. CONSLUSIONS: Increased expression of SDC4 and FN may be underlying molecular alteration of osteosarcoma which accounts for more aggressive clinical behaviour.', 'http://www.ncbi.nlm.nih.gov/pubmed/22531343', 'yes', 'yes', 'NA', 2),
(22534782, 'Tang QL, Xie XB, Wang J, Chen Q, Han AJ, Zou CY, Yin JQ, Liu DW, Liang Y, Zhao ZQ, Yong BC, Zhang RH, Feng QS, Deng WG, Zhu XF, Zhou BP, Zeng YX, Shen JN, Kang T', 'Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.', 'J Natl Cancer Inst', '2012', 'Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma. Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent.We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5-8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3β activity with overall survival.Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3β formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3β had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3β resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3β resulted in inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination treatments with GSK-3β inhibitors, NF-κB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3β, and nuclear NF-κB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3β and NF-κB (109.2 months).GSK-3β activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3β and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22534782', 'no', 'no', 'NA', 2),
(22542077, 'Gallagher R, Keighley J, Tancabelic J, Garimella R, Pinson D, Templeton K, Tawfik O', 'Clinicopathologic correlation of vitamin D receptor expression with retinoid X receptor and MIB-1 expression in primary and metastatic osteosarcoma.', 'Ann Diagn Pathol', '2012', 'Clinicopathologic correlation of vitamin D receptor expression with retinoid X receptor and MIB-1 expression in primary and metastatic osteosarcoma. Vitamin D, in addition to its effects on bone, is important in cell cycle regulation. Vitamin D receptor (VDR) has been identified in breast, prostate, and colon cancers, as well as in canine and human osteosarcoma (OS) cell lines; however, it has not been well investigated in human OS-archived specimens. We correlated VDR, retinoid X receptor (RXR), and MIB-1 (Ki-67) expression in 110 archived OS cases with several clinicopathologic parameters including patient''s age, sex, tumor location, tumor grade, and type and metastatic status. The expression of VDR and RXR was identified in human OS tissue obtained from primary and metastatic OS archival tissue. No statistically significant difference was found in VDR expression in relation with tumor grade, type, age, sex, or location. The expression of RXR was highest in higher-grade (P = .0006) and metastatic tumors but remained unchanged when correlated with tumor type, age, sex, or location. The expression of MIB-1 was statistically elevated in higher-grade tumors (P = .001), patients 25 years or younger (P = .04), tumors located in extremities (P = .005), and metastatic lesions, but was not impacted by tumor type or patient''s sex. Proliferative activity was significantly reduced after treatment, as the mean MIB-1 expression dropped from 11% in primary biopsy samples to 6% in resection specimens. There appears to be a relationship between proliferative tumor activity and tumor grade, location, and metastasis. Additional studies on the analysis of the effects of vitamin D and RXR on OS proliferation, apoptosis, and differentiation are critical to further evaluate their potential role in OS treatment.Copyright © 2012 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22542077', 'yes', 'yes', 'NA', 3),
(22542792, 'Guo XG, Liu CT, Dai H, Guo QN', 'Mutations in the mitochondrial ATPase6 gene are frequent in human osteosarcoma.', 'Exp Mol Pathol', '2013', 'Mutations in the mitochondrial ATPase6 gene are frequent in human osteosarcoma. To explore the polymorphisms and mutations of mitochondrial ATPase6 gene in Chinese patients with osteosarcoma and their possible association with carcinogenesis, direct DNA sequencing method was used to detect the variants of the mitochondrial ATPase6 gene in 39 patients with osteosarcoma. We found mutations of the mitochondrial ATPase6 gene in 24/39 (61.5%) of the tested osteosarcoma samples, and identified 27 variant sites in ATPase6 coding regions. We did not detect any new polymorphisms in osteosarcoma, nor was there any association between variants and the three histopathological subtypes. These data demonstrated that mtDNA mutations within the ATPase6 gene are a frequent event in Chinese patients with osteosarcoma.Copyright © 2012. Published by Elsevier Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/22542792', 'yes', 'no', 'NA', 1);

INSERT INTO `pm` (`pmid`, `author`, `title`, `journal`, `year`, `abstract`, `url`, `tumor`, `value`, `addon`, `frequency`) VALUES
(22870217, 'Saini V, Hose CD, Monks A, Nagashima K, Han B, Newton DL, Millione A, Shah J, Hollingshead MG, Hite KM, Burkett MW, Delosh RM, Silvers TE, Scudiero DA, Shoemaker RH', 'Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma.', 'PLoS One', '2012', 'Identification of CBX3 and ABCA5 as putative biomarkers for tumor stem cells in osteosarcoma. Recently, there has been renewed interest in the role of tumor stem cells (TSCs) in tumorigenesis, chemoresistance, and relapse of malignant tumors including osteosarcoma. The potential exists to improve osteosarcoma treatment through characterization of TSCs and identification of therapeutic targets. Using transcriptome, proteome, immunophenotyping for cell-surface markers, and bioinformatic analyses, heterogeneous expression of previously reported TSC or osteosarcoma markers, such as CD133, nestin, POU5F1 (OCT3/4), NANOG, SOX2, and aldehyde dehydrogenase, among others, was observed in vitro. However, consistently significantly lower CD326, CD24, CD44, and higher ABCG2 expression in TSC-enriched as compared with un-enriched osteosarcoma cultures was observed. In addition, consistently higher CBX3 expression in TSC-enriched osteosarcoma cultures was identified. ABCA5 was identified as a putative biomarker of TSCs and/or osteosarcoma. Lastly, in a high-throughput screen we identified epigenetic (5-azacytidine), anti-microtubule (vincristine), and anti-telomerase (3,11-difluoro-6,8,13-trimethyl- 8H-quino [4,3,2-kl] acridinium methosulfate; RHPS4)-targeted therapeutic agents as candidates for TSC ablation in osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22870217', 'no', 'no', 'NA', 10),
(22870593, 'El-Badawi ZH, Muhammad EM, Noaman HH', 'Role of immunohistochemical cyclo-oxygenase-2 (COX-2) and osteocalcin in differentiating between osteoblastomas and osteosarcomas.', 'Malays J Pathol', '2012', 'Role of immunohistochemical cyclo-oxygenase-2 (COX-2) and osteocalcin in differentiating between osteoblastomas and osteosarcomas. Differential diagnosis between aggressive osteoblastoma and low grade osteosarcoma may be very difficult or even impossible on a small biopsy. This study was designed to assess the usefulness of immunoexpression of COX-2 and osteocalcin in the differential diagnosis of the two tumour types.Immunostaining of COX 2 and osteocalcin were studied in 9 osteoblastomas and 30 osteosarcomas.All osteoblastomas and 11/20 (55%) high-grade osteosarcomas showed COX-2 immunoreactivity. All low grade osteosarcomas were COX-2 negative. COX-2 was significantly higher (p<0.002) in osteoblastomas 9/9 (100%) than in osteosarcomas 13/30 (43%) and in aggressive osteoblastomas versus low grade osteosarcomas (p<0.01). Osteocalcin was found in tumour cells of all osteosarcomas and osteoblastomas and in the osteoid matrix of 84% of osteosarcomas and 78% of osteoblastomas. Strong osteocalcin was significantly higher (p<0.02) in osteoblastomas (78%) than in osteosarcomas (27%).COX-2 is a valuable marker in distinction between osteosarcoma and osteoblastoma. Negative COX-2 could confirm the diagnosis of low grade osteosarcoma versus aggressive osteoblastoma. Intensity and distribution of osteocalcin may indicate the degree of osteoblastic differentiation.', 'http://www.ncbi.nlm.nih.gov/pubmed/22870593', 'yes', 'yes', 'NA', 2),
(22886393, 'Meng Q, Zheng M, Liu H, Song C, Zhang W, Yan J, Qin L, Liu X', 'TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell.', 'Mol Cell Biochem', '2012', 'TRAF6 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. TRAF6, a unique tumor necrosis factor receptor-associated factor (TRAF) family member, possesses a unique receptor-binding specificity that results in its crucial role as the signaling mediator for TNF receptor superfamily and interleukin-1 receptor/Toll-like receptor superfamily. TRAF6 plays an important role in tumorigenesis, invasion and metastasis. This study aimed to explore the expression of TRAF6 in osteosarcoma tissues and its correlation to the clinical pathology of osteosarcoma and to discuss the relationship between TRAF6 expression and osteosarcoma invasion. These data will provide the experimental base for the biological treatment of osteosarcoma in the future. Using RT-PCR and Western blot, the results showed that the expression rate of TRAF6 mRNA in osteosarcoma tissues was significantly higher than that in normal bone tissue (p < 0.05), that the expression rate of TRAF6 mRNA in the carcinoma tissues from patients with lung metastasis was significantly higher than that from patients without lung metastasis (p < 0.05), and that the expression rate of TRAF6 mRNA also increased with increasing Enneking stage (p < 0.05). However, the mRNA expression of TRAF6 in osteosarcoma was independent of the patient''s gender, age, and tumor size (p > 0.05). The TRAF6 protein displayed an up-regulation in osteosarcoma tissues compared to normal bone tissue (p < 0.05), displayed an up-regulation in osteosarcoma tissues from patients with lung metastasis compared to from patients without lung metastasis (p < 0.05), and displayed a gradual increase with increasing Enneking stage (p < 0.05). By the technique of RNA interference, the expression of TRAF6 in the human osteosarcoma MG-63 cell line was down-regulated, and the invasive ability of MG-63 cells was examined. The results showed that TRAF6 protein expression was significantly decreased in the MG-63 cells from TRAF6 siRNA-transfected group (p < 0.05), and the proliferation ability of MG-63 cells and the number of MG-63 cells that passed through the Transwell chamber were significantly lower than that in the non-transfected control group as well as the transfected control group (p < 0.05). In addition, the percentage of MG-63 cells undergoing apoptosis was significantly higher in the TRAF6 siRNA-transfected group compared with the non-transfected control group as well as the transfected control group (p < 0.05). The expression of p-p65, cyclin D1, MMP-9 was down-regulated in the MG-63 cells from TRAF6 siRNA-transfected group. The expression of caspase 3 was up-regulated in the MG-63 cells from TRAF6 siRNA-transfected group compared to the non-transfected control group as well as the transfected control group (p < 0.05). To make a long story short, the overexpression of TRAF6 in osteosarcoma might be related to the tumorigenesis, invasion of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22886393', 'yes', 'no', 'NA', 5),
(22889802, 'Lombardo CM, Welsh SJ, Strauss SJ, Dale AG, Todd AK, Nanjunda R, Wilson WD, Neidle S', 'A novel series of G-quadruplex ligands with selectivity for HIF-expressing osteosarcoma and renal cancer cell lines.', 'Bioorg Med Chem Lett', '2012', 'A novel series of G-quadruplex ligands with selectivity for HIF-expressing osteosarcoma and renal cancer cell lines. A series of naphthalene derivatives with disubstituted triazole side-arms have been assembled by click chemistry. Lead compounds show a high level of selectivity for renal, osteo- and Ewing''s sarcomas that express the HIF-1α transcription factor. They also interact selectively with the quadruplex DNAs located in the promoter of the HIF genes and it is suggested that the mechanism of action involves inhibition of transcription by drug-mediated quadruplex stabilization in these regions.Copyright © 2012 Elsevier Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22889802', 'no', 'no', 'naphthalene derivatives', 1),
(22911823, 'Liu Y, Lv B, He Z, Zhou Y, Han C, Shi G, Gao R, Wang C, Yang L, Song H, Yuan W', 'Lysyl oxidase polymorphisms and susceptibility to osteosarcoma.', 'PLoS One', '2012', 'Lysyl oxidase polymorphisms and susceptibility to osteosarcoma. Despite the knowledge of many genetic alterations present in osteosarcoma, the complexity of this disease precludes placing its biology into a simple conceptual framework. Lysyl oxidase (LOX) catalyzes the cross-linking of elastin and collagen, which is essential for the structural integrity and function of bone tissue. In the current study, we performed genomic sequencing on all seven exons--including the intron-exon splice sites, and the putative promoter region of LOX gene--followed by luciferase reporter assay to analyze the function of newly identified polymorphisms. Associations between LOX polymorphisms and osteosarcoma were then evaluated. Our sequencing data revealed three polymorphisms (-22G/C, 225C/G, and 473G/A) in the exons and promoter region of LOX. The -22G/C polymorphism lies in the downstream core promoter element (DPE) region and caused a decrease in promoter activity of LOX. The prevalence of the -22C allele and 473A allele were significantly increased in osteosarcoma patients compared to controls (odds ratio [OR] = 3.88, 95% confidence interval [CI]= 1.94-7.78, p = 4.18×10(-5), and OR = 1.38, 95%CI = 1.07-1.78, p = 0.013; p 0.0167 was considered significant after Bonferroni correction). Analyzing haplotype showed that the frequency of CCG haplotype (-22, 225, 473) was significantly higher in osteosarcoma cases than in healthy controls after Bonferroni correction (p = 4.46×10(-4)). These results indicate that the -22G/C polymorphism may affect the expression of LOX, and that -22G/C and 473G/A polymorphisms may be new risk factors for osteosarcoma. These findings reveal a potential new pathway by which genetic polymorphisms may affect human diseases.', 'http://www.ncbi.nlm.nih.gov/pubmed/22911823', 'yes', 'yes', 'NA', 1),
(22916108, 'Kleinschmidt MA, de Graaf P, van Teeffelen HA, Timmers HT', 'Cell cycle regulation by the PRMT6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors.', 'PLoS One', '2012', 'Cell cycle regulation by the PRMT6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors. PRMT6 belongs to the family of Protein Arginine Methyltransferase (PRMT) enzymes that catalyze the methylation of guanidino nitrogens of arginine residues. PRMT6 has been shown to modify the tail of histone H3, but the in vivo function of PRMT6 is largely unknown. Here, we show that PRMT6 regulates cell cycle progression. Knockdown of PRMT6 expression in the human osteosarcoma cell line U2OS results in an accumulation of cells at the G2 checkpoint. Loss of PRMT6 coincides with upregulation of p21 and p27, two members of the CIP/KIP family of cyclin-dependent kinase (CDK) inhibitors. Gene expression and promoter analysis show that p21 and p27 are direct targets of PRMT6, which involves methylation of arginine-2 of histone H3. Our findings imply arginine methylation of histones by PRMT6 in cell cycle regulation.', 'http://www.ncbi.nlm.nih.gov/pubmed/22916108', 'no', 'no', 'NA', 3),
(22922684, 'Duan DP, Dang XQ, Wang KZ, Wang YP, Zhang H, You WL', 'The cyclooxygenase-2 inhibitor NS-398 inhibits proliferation and induces apoptosis in human osteosarcoma cells via downregulation of the survivin pathway.', 'Oncol Rep', '2012', 'The cyclooxygenase-2 inhibitor NS-398 inhibits proliferation and induces apoptosis in human osteosarcoma cells via downregulation of the survivin pathway. Cyclooxygenase-2 (COX-2) is frequently overexpressed in human malignancies and plays a crucial role in tumorigenesis and cancer progression. The present study aimed to investigate the expression and clinical significance of COX-2 and survivin (SUV) in human osteosarcomas (OS), and explore the effects and molecular mechanisms of a selective COX-2 inhibitor NS-398 and SUV on tumor proliferation and apoptosis. Fifty cases of human OS and osteochondromas (OC) were collected. The expression of COX-2 and SUV was assessed using immunohistochemical assays in biopsy samples. MG-63 human OS cells were treated with different concentrations of NS-398, used to investigate their effects on cell proliferation and apoptosis. The recombinant small hairpin RNA adenovirus vector rAd5-SUV was constructed, and the effects and molecular mechanisms of knockdown of SUV on proliferation and apoptosis were evaluated in MG-63 cells. A subcutaneous xenograft tumor model was established, validating the effects of rAd5-SUV on tumor growth in vivo. Based on the results, the expression of COX-2 and SUV in OS showed a higher strong reactivity rate compared with OC (73.3 vs. 25.0%, P=0.001; 63.3 vs. 30.0%, P=0.02), but it did not correlate with the clinicopathological characteristics of OS. NS-398 inhibited proliferation, induced apoptosis and decreased the mRNA expression of COX-2 and SUV in MG-63 cells. Furthermore, adenovirus-mediated knockdown of SUV inhibited proliferation, induced apoptosis, reduced the expression of proliferating cell nuclear antigen (PCNA), increased the expression of caspase-3 (CAS-3) and slowed the growth of xenograft tumors in MG-63 cells. Taken together, the expression of COX-2 and SUV is closely correlated with human OS, and inhibition of COX-2 or knockdown of SUV suppresses tumor proliferation and induces apoptosis, suggesting that COX-2 may be involved in OS cell proliferation and apoptosis through SUV-mediated regulation of PCNA and CAS-3 expression, and provides a potential therapeutic strategy for the treatment of cancer.', 'http://www.ncbi.nlm.nih.gov/pubmed/22922684', 'yes', 'no', 'NS-398', 4),
(22922800, 'Zhao H, Guo M, Zhao G, Ma Q, Ma B, Qiu X, Fan Q', 'miR-183 inhibits the metastasis of osteosarcoma via downregulation of the expression of Ezrin in F5M2 cells.', 'Int J Mol Med', '2012', 'miR-183 inhibits the metastasis of osteosarcoma via downregulation of the expression of Ezrin in F5M2 cells. Osteosarcoma is the most common primary malignancy of bone in teenagers and approximately 30% of patients develop lung metastasis, which is the leading cause of mortality. Recent studies suggest that the Ezrin protein is correlated with the metastatic potential of several malignant tumors. In our study, ectopic overexpression of miR-183 repressed the expression levels of Ezrin and significantly inhibited the motility and invasion of osteosarcoma cells. This suggests that miR-183 may possibly play a tumor suppressor role in the metastasis of osteosarcoma by downregulating Ezrin expression levels. These findings show that through inhibition of Ezrin expression levels, miR-183 is significantly involved in cell migration and invasion of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22922800', 'no', 'no', 'NA', 2),
(22922827, 'Cai CK, Zhao GY, Tian LY, Liu L, Yan K, Ma YL, Ji ZW, Li XX, Han K, Gao J, Qiu XC, Fan QY, Yang TT, Ma BA', 'miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma.', 'Oncol Rep', '2012', 'miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma. Osteosarcoma, the most common primary tumor of the bones, causes many deaths due to its rapid proliferation and drug resistance. Recent studies have shown that cyclin D1 plays a key regulatory role during cell proliferation, and non-coding microRNAs (miRNAs) act as crucial modulators of cyclin D1 (CCND1). The aim of the current study was to determine the role of miRNAs in controlling CCND1 expression and inducing cell apoptosis. CCND1 has been found to be a target of miR-15a and miR-16-1 through analysis of complementary sequences between microRNAs and CCND1 mRNA. The upregulation of miR-15a and miR-16-1 in the cell line SOSP-9607 induces apoptosis and cell cycle arrest. Osteosarcoma cells transfected with miR-15a and miR-16-1 show slower proliferation curves. Moreover, the transcription of CCND1 is suppressed by miR-15a and miR-16-1 via direct binding to the CCND1 3''-untranslated region (3''-UTR). The data presented here demonstrate that the CCND1 contributes to osteosarcoma cell proliferation, suggesting that repression of CCND1 by miR-15a and miR-16-1 could be used for osteosarcoma therapy.', 'http://www.ncbi.nlm.nih.gov/pubmed/22922827', 'no', 'no', 'NA', 3),
(22923031, 'Yamanegi K, Yamane J, Kobayashi K, Ohyama H, Nakasho K, Yamada N, Hata M, Fukunaga S, Futani H, Okamura H, Terada N', 'Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells.', 'Oncol Rep', '2012', 'Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells. Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/22923031', 'no', 'no', 'valproic acid', 4),
(22926753, 'Wang CT, Lin CS, Shiau CW, Chu PY, Hsiao CC, Chiang YL, Tai WT, Chen KF', 'SC-1, a sorafenib derivative, shows anti-tumor effects in osteogenic sarcoma cells.', 'J Orthop Res', '2013', 'SC-1, a sorafenib derivative, shows anti-tumor effects in osteogenic sarcoma cells. Despite significant advances in the treatment of osteosarcoma (OS), overall survival rate of OS patients has remained relatively constant for over two decades and novel approaches are needed to further improve prognosis. Here, we report the anti-tumor effect of SC-1, a novel sorafenib derivative that closely resembles sorafenib structurally but is devoid of kinase inhibitory activity, on OS cells through mediation of signal transducer and activator of transcription 3 (STAT3). SC-1 showed similar effects to sorafenib on growth inhibition and apoptosis, and downregulated phospho-STAT3 (p-STAT3) at tyrosine 705 in all tested OS cell lines (U2OS, HOS, and 143B). Expression of STAT3-driven genes, including cylcin D1 and c-myc, were also repressed by SC-1. Ectopic expression of STAT3 in 143B cells abolished apoptosis in SC-1-treated cells. Inhibition of SHP-1 decreased SC-1-induced apoptosis. SC-1 upregulated the activity of SHP-1 in tested OS cell lines in a dose-dependent manner. Finally, SC-1 reduced 143B tumor growth significantly in vivo, which was associated with downregulation of p-STAT3 and upregulation of SHP-1 activity. These data demonstrate that SC-1 has clinical potential for the treatment of OS patients.Copyright © 2012 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/22926753', 'no', 'no', 'sorafenib derivative', 4),
(22935974, 'Na KY, Kim YW, Park YK', 'Mitogen-activated protein kinase pathway in osteosarcoma.', 'Pathology', '2012', 'Mitogen-activated protein kinase pathway in osteosarcoma. The MAPK pathway has been shown to contribute to the prognostic role and drug resistance in many cancers. In addition, the MAPK pathway was found to play a role in the aggressive behaviour of osteosarcoma (OS). We hypothesised that the expression of the MAPK pathway components may be of value in predicting the prognosis of patients with OS.We evaluated the expression of pan-Ras, Raf-1, pMEK1/2 and pERK1/2 in 61 OS samples using immunohistochemistry and evaluated their effect on event free survival (EFS) and overall survival (OVS).pan-Ras, Raf-1, pMEK1/2 and pERK1/2 were found to be expressed in seven (11%), 36 (59%), 36 (59%) and 30 (49%) of 61 samples, respectively. Patients groups whose tumours expressed Raf-1, pMEK1/2 or pERK1/2 had a poorer clinical outcome than the group whose tumours did not express those antibodies. In addition, positive pMEK1/2 expression was associated with shorter EFS and OVS, irrespective of other prognostic factors.Our results further support the findings that aberrant expression of the MAPK pathway components may be the underlying mechanism behind OS, which results in more aggressive clinical behaviour. Furthermore, there may be a decrease in EFS and OVS in OS patients who have tumours that stain positively for pMEK.', 'http://www.ncbi.nlm.nih.gov/pubmed/22935974', 'yes', 'yes', 'NA', 5),
(22938445, 'Zhang SL, Mao NF, Sun JY, Shi ZC, Wang B, Sun YJ', 'Predictive potential of glutathione S-transferase polymorphisms for prognosis of osteosarcoma patients on chemotherapy.', 'Asian Pac J Cancer Prev', '2012', 'Predictive potential of glutathione S-transferase polymorphisms for prognosis of osteosarcoma patients on chemotherapy. To evaluate the predictive value of glutathione S-transferase (GST) gene polymorphisms for the prognosis of osteosarcoma patients receiving chemotherapy.A total of 159 patients were included in our study between January 2005 and December 2007., with follow-up until January 2012. Genotyping was based upon the duplex polymerase-chain-reaction with the PCR-CTPP method.At the time of diagnosis, 15.4% of the patients presented with metastasis, while 22.3% developed metastasis during follow-up. At the time of final analysis on January 2012, the median follow-up was 45.5 months. Patients with null GSTM1 and GSTT1 had a higher event free survival rate than non-null genotype, but no significant association was found between the two genotypes and prognosis of osteosarcoma. Individuals with GSTP1 Val/Val genotype tended to live shorter than with the IIe/IIe genotype, and we found a significantly higher risk of death from osteosarcoma (adjusted HR=2.35, 95% CI=1.13-4.85).The GSTP1 gene polymorphism may have an important role in the prognosis of osteosarcoma patients with chemotherapy. Further analyses with larger samples and more genes encoding metabolizing and DNA repair enzymes are warranted.', 'http://www.ncbi.nlm.nih.gov/pubmed/22938445', 'yes', 'yes', 'NA', 3),
(22939995, 'Lin YM, Chang ZL, Liao YY, Chou MC, Tang CH', 'IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma.', 'Cancer Lett', '2013', 'IL-6 promotes ICAM-1 expression and cell motility in human osteosarcoma. Osteosarcoma is characterized by a high malignant and metastatic potential. Interleukin-6 (IL-6) is a multifunctional cytokine that is associated with the disease status and outcomes of cancers. However, the effect of IL-6 on migration activity in human osteosarcoma cells is mostly unknown. Here we found that IL-6 increased the migration and expression of intercellular adhesion molecule-1 (ICAM-1) in human osteosarcoma cells. Transfection of cells with ICAM-1 siRNA reduced IL-6-mediated cell migration. We also found that expression of IL-6 was significantly greater in human osteosarcoma tissues than in normal bone. The integrin-linked kinase (ILK)/Akt/AP-1 pathway was activated after IL-6 treatment, and IL-6-induced expression of ICAM-1 and migration activity was inhibited by the specific inhibitor and siRNA of ILK, Akt, and AP-1 cascades. In addition, over-expression of IL-6 shRNA inhibited the migratory ability and ICAM-1 expression in osteosarcoma cells. Taken together, these results indicate that IL-6 and IL-6 receptor interaction occurs through ILK and Akt, which in turn activates AP-1, resulting in the activations of ICAM-1 and contributing the migration of human osteosarcoma cells.Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/22939995', 'yes', 'no', 'NA', 6),
(22948234, 'Li B, Yang Y, Jiang S, Ni B, Chen K, Jiang L', 'Adenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3K/AKT pathway.', 'Int J Oncol', '2012', 'Adenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3K/AKT pathway. Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily of signaling molecules and have previously been shown to be associated with the biological behavior of osteosarcoma. However, to date the effects and molecular mechanisms of BMP-9 on osteosarcoma progression are unknown. We performed real-time PCR and western blot analysis to characterize the endogenous expression of BMP-9 in osteosarcoma cell lines. We used a recombinant adenovirus expressing BMP-9 (adBMP-9) to infect osteosarcoma cell lines with relatively low endogenous BMP-9 expression to determine the functional relevance of BMP-9 overexpression to osteosarcoma cell growth and migration in vitro and in vivo, and further investigated the expression levels of Ki-67, matrix metallopeptidase-9 (MMP-9), phosphoinositide 3-kinase p85α (PI3Kp85α) and phosphorylated AKT (p-AKT). As a result, osteosarcoma cell proliferation and migration were significantly diminished by adBMP-9, indicated by MTT and wound-healing assays, and cell apoptosis was markedly induced, indicated by Hoechst 33342/PI assay and Annexin V-FITC apoptosis detection. When BMP-9 expression was enhanced, the expression of PI3Kp85α, p-AKT, Ki-67 and MMP-9 was downregulated in osteosarcoma cells. In addition, the tumor volumes in MG-63 and HOS subcutaneous nude mouse models treated with adBMP-9 were significantly smaller compared to those of the ad-GFP group. These results suggested that the enhanced expression of BMP-9 in osteosarcoma cells by adBMP-9 exerted inhibitory effects on growth and migration of osteosarcoma cells possibly via blockade of the PI3K/AKT signaling pathway.', 'http://www.ncbi.nlm.nih.gov/pubmed/22948234', 'no', 'no', 'NA', 3),
(22949168, 'Lucero CM, Vega OA, Osorio MM, Tapia JC, Antonelli M, Stein GS, van Wijnen AJ, Galindo MA', 'The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines.', 'J Cell Physiol', '2013', 'The cancer-related transcription factor Runx2 modulates cell proliferation in human osteosarcoma cell lines. Runx2 regulates osteogenic differentiation and bone formation, but also suppresses pre-osteoblast proliferation by affecting cell cycle progression in the G(1) phase. The growth suppressive potential of Runx2 is normally inactivated in part by protein destabilization, which permits cell cycle progression beyond the G(1)/S phase transition, and Runx2 is again up-regulated after mitosis. Runx2 expression also correlates with metastasis and poor chemotherapy response in osteosarcoma. Here we show that six human osteosarcoma cell lines (SaOS, MG63, U2OS, HOS, G292, and 143B) have different growth rates, which is consistent with differences in the lengths of the cell cycle. Runx2 protein levels are cell cycle-regulated with respect to the G(1)/S phase transition in U2OS, HOS, G292, and 143B cells. In contrast, Runx2 protein levels are constitutively expressed during the cell cycle in SaOS and MG63 cells. Forced expression of Runx2 suppresses growth in all cell lines indicating that accumulation of Runx2 in excess of its pre-established levels in a given cell type triggers one or more anti-proliferative pathways in osteosarcoma cells. Thus, regulatory mechanisms controlling Runx2 expression in osteosarcoma cells must balance Runx2 protein levels to promote its putative oncogenic functions, while avoiding suppression of bone tumor growth.Copyright © 2012 Wiley Periodicals, Inc.', 'http://www.ncbi.nlm.nih.gov/pubmed/22949168', 'no', 'no', 'NA', 1),
(22968906, 'Yang W, Liu X, Choy E, Mankin H, Hornicek FJ, Duan Z', 'Targeting hedgehog-GLI-2 pathway in osteosarcoma.', 'J Orthop Res', '2013', 'Targeting hedgehog-GLI-2 pathway in osteosarcoma. Osteosarcoma is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many of these patients eventually relapse after these treatments. In such cases, there are limited treatment options for these patients and most will eventually die with metastatic disease. Therefore, it is imperative to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of vertebrate embryonic and tumorigenesis. Specifically, the transcription factor, GLI-2, plays a key role in development of normal prostate. Aberrant activation of GLI-2 is correlated with various malignancies. We observe that GLI-2 is highly expressed in osteosarcoma cell lines, and this correlates with poor clinical outcomes in patients. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation and viability, which eventually induces cell death as revealed in both in 2D and 3D cultures. In addition, we notice that administration of GLI-2 siRNA can increase the sensitivity of osteosarcoma cells to chemotherapeutic drugs. These findings suggest GLI-2 is required for osteosarcoma cell proliferation and survival. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients.Copyright © 2012 Orthopaedic Research Society.', 'http://www.ncbi.nlm.nih.gov/pubmed/22968906', 'yes', 'yes', 'NA', 1),
(22992985, 'Yamada N, Yamanegi K, Ohyama H, Hata M, Nakasho K, Futani H, Okamura H, Terada N', 'Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1α-dependent manner.', 'Int J Oncol', '2012', 'Hypoxia downregulates the expression of cell surface MICA without increasing soluble MICA in osteosarcoma cells in a HIF-1α-dependent manner. Tumor cells express NKG2D ligands on their cell surface, which are the ligands of the activating receptor, NKG2D, that is expressed on the surface of NK cells. The binding of NK cells to tumor cells through the interaction of NKG2D and its ligands induces the cytolysis of the tumor cells. In the present study, we investigated the effects of hypoxia on the expression of NKG2D ligands on the surface of human osteosarcoma cells using three cell lines. To produce hypoxic and normoxic conditions, the osteosarcoma cell lines were cultured under 1 and 20% O2 conditions, respectively. The osteosarcoma cells expressed NKG2D ligands such as MHC class I-related chain molecules A and B (MICA and MICB) and the UL16-binding proteins 1, 2 and 3 (ULBP 1, 2 and 3). MICA was the most frequently expressed NKG2D ligand in the osteosarcoma cells. Hypoxia decreased the expression of cell surface MICA only without increasing the secretion of soluble MICA, which is produced by proteolytic cleavage of cell surface MICA. Hypoxia consistently decreased the susceptibility of the osteosarcoma cells to the cytotoxicity of the NK cells. Hypoxia induced the expression of hypoxia-inducible factor-1α (HIF-1α), and knockdown of the expression of HIF-1α using small interfering RNA increased the expression of cell surface MICA and concomitantly increased the level of soluble MICA. Hypoxia decreased the production of nitric oxide (NO) metabolites (nitrite and nitrate), thus, indicating a decreasing effect on NO production. However, a NO donor, NOC18, decreased the expression of cell surface MICA without any apparent effects on the expression of HIF-1α under both hypoxic and normoxic conditions. The present results indicate that hypoxia downregulates the expression of cell surface MICA without increasing the level of soluble MICA in a HIF-1α-dependent manner and suggest that the effects of hypoxia are not linked to the hypoxia-induced reduction of NO production.', 'http://www.ncbi.nlm.nih.gov/pubmed/22992985', 'no', 'no', 'NA', 6),
(22993301, 'Miwa S, Sugimoto N, Yamamoto N, Shirai T, Nishida H, Hayashi K, Kimura H, Takeuchi A, Igarashi K, Yachie A, Tsuchiya H', 'Caffeine induces apoptosis of osteosarcoma cells by inhibiting AKT/mTOR/S6K, NF-κB and MAPK pathways.', 'Anticancer Res', '2012', 'Caffeine induces apoptosis of osteosarcoma cells by inhibiting AKT/mTOR/S6K, NF-κB and MAPK pathways. We previously reported that caffeine-assisted chemotherapy improved the treatment of malignant bone and soft tissue tumours such as osteosarcoma. Caffeine affects tumour cells through various pathways, including phosphatase and tensin homolog deleted on chromosome 10 (PTEN), AKT, Bcl-2-associated X protein (BAX), caspase-3 and p53, and has therefore been indicated as being useful for the treatment of malignant tumours. Here, the effects of caffeine on the proliferation of HOS osteosarcoma cells were assessed by WST-8 assay, and the effects on the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways were assessed by western blot analyses. Caffeine inhibited proliferation of HOS cells and suppressed NF-κB, AKT, mTOR/S6K and ERK activities. Our results support those from previous studies relating to the use of caffeine in the treatment of osteosarcoma.', 'http://www.ncbi.nlm.nih.gov/pubmed/22993301', 'no', 'no', 'caffeine', 5),
(22994717, 'Gong C, Liao H, Wang J, Lin Y, Qi J, Qin L, Tian LQ, Guo FJ', 'LY294002 induces G0/G1 cell cycle arrest and apoptosis of cancer stem-like cells from human osteosarcoma via down-regulation of PI3K activity.', 'Asian Pac J Cancer Prev', '2012', 'LY294002 induces G0/G1 cell cycle arrest and apoptosis of cancer stem-like cells from human osteosarcoma via down-regulation of PI3K activity. Osteosarcoma, the most common primary mesenchymal malignant tumor, usually has bad prognosis in man, with cancer stem-like cells (CSCs) considered to play a critical role in tumorigenesis and drug-resistance. It is known that phosphatidylinositol 3-kinase (PI3K) is involved in regulation of tumor cell fates, such as proliferation, cell cycling, survival and apoptosis. Whether and how PI3K and inhibitors might cooperate in human osteosarcoma CSCs is still unknown. We therefore evaluated the effects of LY294002, a PI3K inhibitor, on the cell cycle and apoptosis of osteosarcoma CSCs in vitro. LY294002 prevented phosphorylation of protein kinase B (PKB/Akt) by inhibition of PI3K phosphorylation activity, thereby inducing G0/G1 cell cycle arrest and apoptosis in osteosarcoma CSCs. Further studies also demonstrated that apoptosis induction by LY294002 is accompanied by activation of caspase-9, caspase-3 and PARP, which are involved in the mitochondrial apoptosis pathway. Therefore, our results indicate PI3K inhibitors may represent a potential strategy for managing human osteosarcoma via affecting CSCs.', 'http://www.ncbi.nlm.nih.gov/pubmed/22994717', 'no', 'no', 'LY294002', 4),
(23000411, 'Hatoh T, Maeda T, Takeuchi K, Ogikubo O, Uchiyama S, Otsuka T, Ohkubo I, Ogita H', 'Domain 5 of high molecular weight kininogen inhibits collagen-mediated cancer cell adhesion and invasion in association with α-actinin-4.', 'Biochem Biophys Res Commun', '2012', 'Domain 5 of high molecular weight kininogen inhibits collagen-mediated cancer cell adhesion and invasion in association with α-actinin-4. High molecular weight kininogen (HK) is a plasma glycoprotein with multiple functions, including the regulation of coagulation. We previously demonstrated that domain 5 (D5(H)), a functional domain of HK, and its derived peptides played an important role in the vitronectin-mediated suppression of cancer cell adhesion and invasion. However, the underlying mechanisms of the D5(H)-mediated suppressive effects remain to be elucidated. Here, we showed that D5(H) and its derivatives inhibited the collagen-mediated cell adhesion and invasion of human osteosarcoma MG63 cells. Using purified D5(H) fused to glutathione-S-transferase (GST) and D5(H)-derived peptides for column chromatography, an actin-binding protein, α-actinin-4, was identified as a binding protein of D5(H) with high-affinity for P-5m, a core octapeptide of D5(H). Immunofluorescence microscopy demonstrated that D5(H) co-localized with α-actinin-4 inside MG63 cells. In addition, exogenous GST-D5(H) added to the culture media was transported into MG63 cells, although GST alone as a control was not. As α-actinin-4 regulates actin polymerization necessary for cell adhesion and is related to the integrin-dependent attachment of cells to the extracellular matrix, our results suggest that D5(H) may modulate cell adhesion and invasion together with actinin-4.Copyright © 2012 Elsevier Inc. All rights reserved.', 'http://www.ncbi.nlm.nih.gov/pubmed/23000411', 'no', 'no', 'NA', 2),
(23015149, 'Rastogi S, Kumar R, Sankineani SR, Marimuthu K, Rijal L, Prakash S, Jalan D, Khan SA, Sharma MC', 'Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study.', 'Int Orthop', '2012', 'Role of vascular endothelial growth factor as a tumour marker in osteosarcoma: a prospective study. A prospective study was undertaken to evaluate the diagnostic and prognostic significance of serum levels of vascular endothelial growth factor (VEGF) in patients with primary localised osteosarcoma.Serum VEGF levels were measured by an enzyme-linked immunosorbent assay (ELISA) in blood samples collected prechemotherapy, postchemotherapy, and postsurgery in 40 patients with histologically proven primary osteosarcoma. Comparison was made between serum VEGF level of healthy controls (n = 10) and prechemotherapy patient sera to evaluate its diagnostic potential. Serum VEGF levels of patients with and without metastasis were compared. Immunohistochemical staining was done to establish the correlation between serum and tissue VEGF expression. The Kaplan-Meier curve was used for survival analysisNo significant relationship was observed between serum VEGF levels and age, gender, tumour size, local recurrence or histopathological subtypes of osteosarcoma. We observed significantly raised mean serum VEGF in patient sera compared with healthy controls (p = 0.001). Significant fall in mean serum VEGF level was observed following chemotherapy (p = 0.001). Patients who developed metastases had significantly higher serum VEGF levels compared with the nonmetastatic group (P = 0.001). Serum VEGF levels correlated well with VEGF expression in tissues.Serum VEGF levels might prove to be of diagnostic, predictive and prognostic value in patients with primary osteosarcoma, although further studies with larger sample size and longer follow-up is needed to support the hypothesis.', 'http://www.ncbi.nlm.nih.gov/pubmed/23015149', 'yes', 'yes', 'NA', 1),
(23027359, 'Nakajima K, Yanagawa T, Watanabe H, Takagishi K', 'Hyperthermia reduces migration of osteosarcoma by suppression of autocrine motility factor.', 'Oncol Rep', '2012', 'Hyperthermia reduces migration of osteosarcoma by suppression of autocrine motility factor. Autocrine motility factor (AMF) plays an important role in the development of metastasis by regulating tumor cell motility. The expression of AMF is associated with metastasis in malignant musculoskeletal tumors including osteosarcoma. Recent studies indicated that hyperthermia contributes to the improvement of the prognosis of patients with soft tissue sarcomas; however, few reports have evaluated the impact of hyperthermia on tumor cell motility, which is an important factor of metastasis. The purpose of this study was to evaluate the effect of hyperthermia with or without heat shock protein (HSP) inhibitors on the motility and AMF expression in an osteosarcoma cell line. Hyperthermia was carried out at 41˚C for 24 h. According to microarray results, HSP90, HSP70 and HSP27 expression was upregulated in osteosarcoma cells under hyperthermia. The intracellular, secreted AMF, mRNA of AMF and cell motility were evaluated by western blotting, ELISA, RT-PCR, wound healing and phagokinetic track assays, respectively. The protein secretion and mRNA levels of AMF and tumor cell motility were significantly decreased by hyperthermia. Of note, the downregulated AMF expression and motility were recovered by the addition of an HSP27 inhibitor. By contrast, the HSP90 and HSP70/72/105 inhibitors had no effect on AMF expression and motility downregulated by hyperthermia. In conclusion, hyperthermia reduced AMF expression and tumor cell motility via HSP27 and may therefore be applied as osteosarcoma treatment.', 'http://www.ncbi.nlm.nih.gov/pubmed/23027359', 'no', 'no', 'NA', 4),
(23045411, 'Posthumadeboer J, van Egmond PW, Helder MN, de Menezes RX, Cleton-Jansen AM, Beliën JA, Verheul HM, van Royen BJ, Kaspers GJ, van Beusechem VW', 'Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin.', 'Oncotarget', '2012', 'Targeting JNK-interacting-protein-1 (JIP1) sensitises osteosarcoma to doxorubicin. Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. Despite aggressive therapy, survival outcomes remain unsatisfactory, especially for patients with metastatic disease or patients with a poor chemotherapy response. Chemoresistance contributes to treatment failure. To increase the efficacy of conventional chemotherapy, essential survival pathways should be targeted concomitantly. Here, we performed a loss-of-function siRNA screen of the human kinome in SaOS-2 cells to identify critical survival kinases after doxorubicin treatment. Gene silencing of JNK-interacting-protein-1 (JIP1) elicited the most potent sensitisation to doxorubicin. This candidate was further explored as potential target for chemosensitisation in OS. A panel of OS cell lines and human primary osteoblasts was examined for sensitisation to doxorubicin using small molecule JIP1-inhibitor BI-78D3. JIP1 expression and JIP1-inhibitor effects on JNK-signalling were investigated by Western blot analysis. JIP1 expression in human OS tumours was assessed by immunohistochemistry on tissue micro arrays. BI-78D3 blocked JNK-signalling and sensitised three out of four tested OS cell lines, but not healthy osteoblasts, to treatment with doxorubicin. Combination treatment increased the induction of apoptosis. JIP1 was found to be expressed in two-thirds of human primary OS tissue samples. Patients with JIP1 positive tumours showed a trend to inferior overall survival. Collectively, JIP1 appears a clinically relevant novel target in OS to enhance the efficacy of doxorubicin treatment by means of RNA interference or pharmacological inhibition.', 'http://www.ncbi.nlm.nih.gov/pubmed/23045411', 'yes', 'no', 'doxorubicin|BI-78D3', 2),
(23052169, 'Je EM, An CH, Yoo NJ, Lee SH', 'Mutational and expressional analyses of NRF2 and KEAP1 in sarcomas.', 'Tumori', 'NA', 'Mutational and expressional analyses of NRF2 and KEAP1 in sarcomas. Nuclear factor erythroid 2-related factor 2 (NRF2) activates expression of cytoprotective proteins such as GCLC and enhances cancer cell survival, whereas KEAP1 inhibits NRF2 by mediating NRF2 degradation. Somatic mutation of NRF2 and KEAP1 genes and loss of KEAP1 expression are detected in many carcinomas and contribute to cancer development. The aim of this study was to see whether mutational and expressional alterations of NRF2 and KEAP1 genes are features of human sarcomas as well.We analyzed somatic mutations of NRF2 and KEAP1 genes in 108 sarcoma tissues from malignant fibrous histiocytomas, rhabdomyosarcomas, osteosarcomas, malignant peripheral nerve sheath tumors, leiomyosarcomas, synovial sarcomas, liposarcomas, angiosarcomas, chondrosarcomas and Ewing sarcomas by single-strand conformation polymorphism. Also, we analyzed expressions of NRF2, KEAP1 and GCLC in sarcoma tissues by immunohistochemistry.Tissue expressions of NRF2 and GCLC were found in 93% and 76% of the sarcomas, respectively, indicating that NRF2 signaling might be activated in most sarcomas. Loss of KEAP1 expression was observed in 24% of the sarcomas, whereas neither NRF2 nor KEAP1 somatic gene mutation was seen in the sarcomas.Our data suggest a possible activation of the NRF2/KEAP1 system in sarcomas and a possible contribution to cytopretection of sarcoma cells.', 'http://www.ncbi.nlm.nih.gov/pubmed/23052169', 'yes', 'no', 'NA', 3),
(23071517, 'Groth-Pedersen L, Aits S, Corcelle-Termeau E, Petersen NH, Nylandsted J, Jäättelä M', 'Identification of cytoskeleton-associated proteins essential for lysosomal stability and survival of human cancer cells.', 'PLoS One', '2012', 'Identification of cytoskeleton-associated proteins essential for lysosomal stability and survival of human cancer cells. Microtubule-disturbing drugs inhibit lysosomal trafficking and induce lysosomal membrane permeabilization followed by cathepsin-dependent cell death. To identify specific trafficking-related proteins that control cell survival and lysosomal stability, we screened a molecular motor siRNA library in human MCF7 breast cancer cells. SiRNAs targeting four kinesins (KIF11/Eg5, KIF20A, KIF21A, KIF25), myosin 1G (MYO1G), myosin heavy chain 1 (MYH1) and tropomyosin 2 (TPM2) were identified as effective inducers of non-apoptotic cell death. The cell death induced by KIF11, KIF21A, KIF25, MYH1 or TPM2 siRNAs was preceded by lysosomal membrane permeabilization, and all identified siRNAs induced several changes in the endo-lysosomal compartment, i.e. increased lysosomal volume (KIF11, KIF20A, KIF25, MYO1G, MYH1), increased cysteine cathepsin activity (KIF20A, KIF25), altered lysosomal localization (KIF25, MYH1, TPM2), increased dextran accumulation (KIF20A), or reduced autophagic flux (MYO1G, MYH1). Importantly, all seven siRNAs also killed human cervix cancer (HeLa) and osteosarcoma (U-2-OS) cells and sensitized cancer cells to other lysosome-destabilizing treatments, i.e. photo-oxidation, siramesine, etoposide or cisplatin. Similarly to KIF11 siRNA, the KIF11 inhibitor monastrol induced lysosomal membrane permeabilization and sensitized several cancer cell lines to siramesine. While KIF11 inhibitors are under clinical development as mitotic blockers, our data reveal a new function for KIF11 in controlling lysosomal stability and introduce six other molecular motors as putative cancer drug targets.', 'http://www.ncbi.nlm.nih.gov/pubmed/23071517', 'no', 'no', 'NA', 7),
(23091618, 'Xie XB, Yin JQ, Wen LL, Gao ZH, Zou CY, Wang J, Huang G, Tang QL, Colombo C, He WL, Jia Q, Shen JN', 'Critical role of heat shock protein 27 in bufalin-induced apoptosis in human osteosarcomas: a proteomic-based research.', 'PLoS One', '2012', 'Critical role of heat shock protein 27 in bufalin-induced apoptosis in human osteosarcomas: a proteomic-based research. Bufalin is the primary component of the traditional Chinese herb \\Chan Su\\. Evidence suggests that this compound possesses potent anti-tumor activities, although the exact molecular mechanism(s) is unknown. Our previous study showed that bufalin inhibited growth of human osteosarcoma cell lines U2OS and U2OS/MTX300 in culture. Therefore, this study aims to further clarify the in vitro and in vivo anti-osteosarcoma effects of bufalin and its molecular mechanism of action. We found bufalin inhibited both methotrexate (MTX) sensitive and resistant human osteosarcoma cell growth and induced G2/M arrest and apoptosis. Using a comparative proteomics approach, 24 differentially expressed proteins following bufalin treatment were identified. In particular, the level of an anti-apoptotic protein, heat shock protein 27 (Hsp27), decreased remarkably. The down-regulation of Hsp27 and alterations of its partner signaling molecules (the decrease in p-Akt, nuclear NF-κB p65, and co-immunoprecipitated cytochrome c/Hsp27) were validated. Hsp27 over-expression protected against bufalin-induced apoptosis, reversed the dephosphorylation of Akt and preserved the level of nuclear NF-κB p65 and co-immunoprecipitated Hsp27/cytochrome c. Moreover, bufalin inhibited MTX-resistant osteosarcoma xenograft growth, and a down-regulation of Hsp27 in vivo was observed. Taken together, bufalin exerted potent anti-osteosarcoma effects in vitro and in vivo, even in MTX resistant osteosarcoma cells. The down-regulation of Hsp27 played a critical role in bufalin-induced apoptosis in osteosarcoma cells. Bufalin may have merit to be a potential chemotherapeutic agent for osteosarcoma, particularly in MTX-resistant groups.', 'http://www.ncbi.nlm.nih.gov/pubmed/23091618', 'no', 'no', 'bufalin', 5);


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-- Tabellenstruktur für Tabelle `pm2cell`
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