Hypoxia increased ovarian cancer invasiveness with increased E-cadherin transcriptional repressor Snail

肿瘤周围微环境在肿瘤发生、发展过程中的作用是近年来研究的热点。我们发现缺氧通过降低E-钙粘蛋白表达增加卵巢癌细胞的侵袭力。本研究旨在探讨缺氧条件下E-cadherin表达下降的机制，通过对卵巢癌细胞株进行缺氧培养，检测E-cadherin表达的变化。在卵巢癌细胞SKOV 3中，E-cadherin的表达在低氧条件下降低。相反，Snail、SIP 1和TWIST（E-cadherin转录抑制因子）的表达在缺氧条件下增加。荧光素酶检测结果表明，缺氧条件下Snail的转录活性比常氧条件下有所提高。针对HIF-1α和HIF-2α的siRNA均能抑制缺氧对snail表达的上调，但HIF-1α的抑制作用强于HIF-2α。HIF-1α siRNA可抑制卵巢癌细胞的侵袭能力，提示卵巢癌细胞通过上调Snail表达，由上皮性向间充质性转化，并增强了缺氧条件下的侵袭能力。

Recent focusing attention is that the surrounding microenvironment plays in the process of tumorigenesis and tumor progression. We found that Hypoxia increased invasiveness of ovarian cancer cells via decreased E-cadherin expression. In this study, we investigate the mechanism of decreased E-cadherin expression under hypoxia.Ovarian cancer cell lines were cultured under hypoxia, and the changes of E-cadherin expression was examined. In ovarian cancer cell (SKOV3), the expression of E-cadherin was decreased under hypoxic condition. In contrast, the expression of Snail, SIP1, and TWIST, E-cadherin transcriptional repressor, were increased under hypoxia. Luciferase assay showed that the transcriptional activity of Snail has increased under hypoxia by compared with under normal oxygen. Although both of siRNA for HIF-1α and HIF-2α inhibited the up-regulation of snail by hypoxia, the effect of HIF-1α was higher than that of HIF-2α. Additionally, the invasiveness of ovarian cancer cells was inhibited by HIF-1α siRNA.These findings suggest that ovarian cancer cells were converted from epithelial character to mesenchymal character and increased invasiveness under hypoxia via upregulation of Snail.