Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells.
Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells.
复制标题
缺氧导致的核转位和 YAP 激活有助于肝癌细胞中 SN38 的化疗耐药
DOI：
10.18632/oncotarget.6903
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发表时间：
2016-02-09
期刊：
影响因子：
--
通讯作者：
He QJ
中科院分区：
文献类型：
--
作者：
Dai XY;Zhuang LH;Wang DD;Zhou TY;Chang LL;Gai RH;Zhu DF;Yang B;Zhu H;He QJ
尽管缺氧是导致肝细胞癌细胞（HCC）对化疗剂（包括拓扑异构酶I抑制剂SN 38）的治疗抗性的突出特征，但其潜在机制尚未完全理解，并且其理解仍然是主要的临床挑战。在本研究中，我们发现缺氧诱导的核移位和雅普积累作为生存输入，促进肝癌对SN 38的耐药性。低氧诱导雅普的表达不是由HIF-1α介导的，因为用CoCl 2、外源性表达和RNA干扰操纵HIF-1α的丰度对雅普的磷酸化或总水平没有影响。甲羟戊酸-HMG-CoA还原酶（HMGCR）途径可能调节缺氧条件下雅普的活化。使用siRNA或HMGCR抑制剂他汀类药物的组合雅普抑制与SN 38处理一起在HCC细胞中产生改善的抗癌作用。他汀类药物和伊立替康（SN-38的前药）联合治疗的抗癌作用增加在裸鼠HCC的人HepG 2异种移植模型中得到进一步验证。综上所述，我们的研究结果确定雅普作为一种新的调解缺氧抗性SN 38。这些结果表明，施用SN 28以及使用他汀类抑制雅普是增强HCC患者，特别是呈现缺氧抗性的晚期HCC病例中的治疗反应的有希望的策略。
Although hypoxia is a prominent feature contributing to the therapeutic resistance of hepatocellular carcinoma cells (HCC) against chemotherapeutic agents, including the Topoisomerase I inhibitor SN38, the underlying mechanism is not fully understood and its understanding remains a major clinical challenge. In the present study, we found that hypoxia-induced nuclear translocation and accumulation of YAP acted as a survival input to promote resistance to SN38 in HCC. The induction of YAP by hypoxia was not mediated by HIF-1α because manipulating the abundance of HIF-1α with CoCl2, exogenous expression, and RNA interference had no effect on the phosphorylation or total levels of YAP. The mevalonate-HMG-CoA reductase (HMGCR) pathway may modulate the YAP activation under hypoxia. Combined YAP inhibition using either siRNA or the HMGCR inhibitor statins together with SN38 treatment produced improved anti-cancer effects in HCC cells. The increased anti-cancer effect of the combined treatment with statins and irinotecan (the prodrug of SN-38) was further validated in a human HepG2 xenograft model of HCC in nude mice. Taken together, our findings identify YAP as a novel mediator of hypoxic-resistance to SN38. These results suggest that the administration of SN28 together with the suppression of YAP using statins is a promising strategy for enhancing the treatment response in HCC patients, particularly in advanced stage HCC cases presenting hypoxic resistance.