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.