Stabilization of Snail by HIF-1α and TNF-α is required for hypoxia-induced invasion in prostate cancer PC3 cells

Hypoxia has been involved in the development of tumor by regulating the expression of invasiveness-associated genes. However, the specific function of hypoxia in cancer cell invasion is still unclear. The aim of the present study was to determine the role of hypoxia in invasion of prostate cancer PC3 cells and to investigate the underlying mechanisms. We found that hypoxia significantly increased the invasive activity of PC3 cells, via up-regulation of the expression of hypoxia inducible factor 1 alpha (HIF-1 alpha) and the autocrine production of tumor necrosis factor alpha (TNF-alpha). More important, TNF-alpha cooperated with HIF-1 alpha in promoting stabilization of Snail, a transcriptional repressor of E-cadherin expression, which lead to the up-regulation of invasiveness-associated genes MMP-9, fibronectin and vimentin. Snail silencing by specific siRNA significantly inhibited hypoxia-induced invasion of PC3 cells, indicating an essential role of Snail in conferring the malignant phenotype to cancer cells under hypoxic conditions. In conclusion, our data demonstrate that hypoxia promoted the invasiveness of prostate cancer PC3 cells via HIF-1 alpha- and TNF-alpha-induced stabilization of Snail, suggesting a signaling mechanism involving HIF-1 alpha/TNF-alpha/Snail that mediates invasiveness hypoxic tumor cells in the absence of neoangiogenesis.