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

近年来人们关注的焦点是周围微环境在肿瘤发生和发展过程中所起的作用。我们发现缺氧通过降低E-cadherin表达增加卵巢癌细胞的侵袭性。在本研究中，我们探讨了低氧条件下E-cadherin表达降低的机制。缺氧培养卵巢癌细胞系，观察E-cadherin表达的变化。在卵巢癌细胞（SKOV3）中，E-cadherin在缺氧条件下表达降低。相比之下，低氧条件下E-cadherin转录抑制因子Snail、SIP1和TWIST的表达增加。荧光素酶测定表明，与正常氧条件下相比，低氧条件下蜗牛的转录活性有所提高。虽然HIF-1α和HIF-2α的siRNA均能抑制缺氧对蜗牛的上调，但HIF-1α的作用高于HIF-2α。此外，HIF-1α siRNA可抑制卵巢癌细胞的侵袭性。这些结果表明，在缺氧条件下，卵巢癌细胞由上皮细胞向间充质细胞转化，并通过上调Snail来增强侵袭性。

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.