Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells

作者：Dai, Xiao-Yang; Zhuang, Lin-Han; Wang, Dan-Dan; Zhou, Tian-Yi; Chang, Lin-Lin; Gai, Ren-Hua; Zhu, Di-Feng; Yang, Bo; Zhu, Hong^*; He, Qiao-Jun^*

来源：Oncotarget, 2016, 7(6): 6933-6947.

DOI：10.18632/oncotarget.6903

• hepatocellular carcinoma
• SN38
• hypoxia
• resistance
• yes-associated protein (YAP)

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-1a because manipulating the abundance of HIF-1a 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.

• 出版日期2016-2-9
• 单位浙江大学