Cisplatin-Induced Sonic Hedgehog Signaling Mediates Epithelial-Mesenchymal Transition In Hertwig'S Epithelial Root Sheath Cells

In this study, we determined whether cisplatin can induce epithelial-mesenchymal transition (EMT) via the activation of Sonic hedgehog (Shh) or glioma-associated antigen-1 (Gli1) signaling pathway in mouse Hertwig's epithelial root sheath (HERS) cells using a genetic knockdown approach. HERS cells treated with a low concentration of cisplatin (0.5 mu M) for 24 h showed no reduction in the cell viability; however, there was a significant increase in the percentages of nuclear staining with gamma H2AX as compared to that with untreated control cells, indicating that 0.5 mu M cisplatin induces DNA damage. Further, 0.5-mu M cisplatin-treated cells provided an induction of EMT, showing decreased and increased expression of epithelial and mesenchymal markers, respectively. Enhancement in the EMT activity in cisplatin-treated HERS cells was correlated with increased expression of Shh and accelerated translocation and accumulation of Gli1 expression into the nucleus. The RNA interference-mediated silencing of Gli1 suppressed the acceleration of EMT in cisplatin-treated HERS cells; this was confirmed by no down-regulation or up-regelation in the expression of E-cadherin and vimentin, respectively, along with no increased expression of Snail expression. These findings suggest that the activation of Shh/Gli1 signaling pathway may be required for the enhancement of EMT in cisplatin-treated HERS cells.