Zhao Chun-Xiong, Luo Chun-Li, Wu Xiao-Hou
Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Med Oncol. 2015 Jan;32(1):419. doi: 10.1007/s12032-014-0419-4. Epub 2014 Dec 7.
Accumulating evidences indicated that hypoxia-induced factors and COX-2 play a important role in tumorigenesis in various human cancer. Yet, the relationship between HIFs and COX-2 in human renal cancer remains unclear. The present study was to examine the role of HIFs and COX-2 in the invasiveness and the resistance to target agent in renal cancer cell line (786-O). In 786-O cells, hypoxia induced the increase in the protein expression of HIF1 and HIF2. We also demonstrate that hypoxia up-regulated the protein expression of COX-2 and Snail, but down-regulation of E-cadherin expression in 786-O cells promoted the invasiveness of 786-O cells and enhanced the resistance of 786-O cells to sorafenib. siRNA target to HIF1α, HIF2α and NS398, a selective inhibitor of COX-2, were used in this study. Only siRNA-HIF2α significantly suppressed the protein expression of HIF2 and COX-2, then decreased the invasive ability and resistance of 786-O cells to sorafenib under hypoxia. NS398 attenuated the increase in invasive cells number and the IC50 value of sorafenib induced by hypoxia. In conclusion, our results demonstrated that hypoxia promoted the invasiveness and resistance of 786-O cells to sorafenib via HIF2 and COX-2 and induced the activation of Snail/E-cadherin, suggesting that a signalling mechanism involving HIF2/COX2 modulates invasiveness and resistance to sorafenib in 786-O cells under hypoxia.
越来越多的证据表明，缺氧诱导因子和环氧化酶-2（COX-2）在多种人类癌症的肿瘤发生中起重要作用。然而，在人类肾癌中，缺氧诱导因子与COX-2之间的关系仍不清楚。本研究旨在探讨缺氧诱导因子和COX-2在肾癌细胞系（786-O）侵袭性及对靶向药物耐药性中的作用。在786-O细胞中，缺氧诱导缺氧诱导因子1（HIF1）和缺氧诱导因子2（HIF2）蛋白表达增加。我们还证明，缺氧上调了786-O细胞中COX-2和Snail的蛋白表达，但E-钙黏蛋白表达下调促进了786-O细胞的侵袭性，并增强了786-O细胞对索拉非尼的耐药性。本研究使用了针对HIF1α、HIF2α的小干扰RNA（siRNA）以及COX-2的选择性抑制剂NS398。只有siRNA-HIF2α显著抑制了HIF2和COX-2的蛋白表达，进而降低了缺氧条件下786-O细胞的侵袭能力及对索拉非尼的耐药性。NS398减弱了缺氧诱导的侵袭细胞数量增加及索拉非尼的半数抑制浓度（IC50）值。总之，我们的结果表明，缺氧通过HIF2和COX-2促进了786-O细胞的侵袭性及对索拉非尼的耐药性，并诱导了Snail/E-钙黏蛋白的激活，提示在缺氧条件下，一种涉及HIF2/COX2的信号机制调节了786-O细胞的侵袭性及对索拉非尼的耐药性。
