COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment
COX-2/PGE2 Axis Regulates HIF2α Activity to Promote Hepatocellular Carcinoma Hypoxic Response and Reduce the Sensitivity of Sorafenib Treatment
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COX-2/PGE2 轴调节 HIF2α 活性，促进肝细胞癌缺氧反应并降低索拉非尼治疗的敏感性。
DOI：
10.1158/1078-0432.ccr-17-2725
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发表时间：
2018-07-01
影响因子：
11.5
通讯作者：
Dong, Zhao-Ru
中科院分区：
文献类型：
--
作者：
Dong, Xiao-Feng;Liu, Tian-Qi;Dong, Zhao-Ru
目的：低氧诱导因子-2 α（HIF 2 α）被认为是个体化肝细胞癌（HCC）治疗和索拉非尼耐药的首选靶点。我们的研究旨在确定低氧条件下HIF 2 α活性的调节机制。我们试图确定考克斯-2/PGE 2轴是否参与HIF 2 α活性和索拉非尼耐药在缺氧HCC cells.Experimental Design中的调节机制：通过测定细胞活力、迁移和侵袭能力来分析HIF 2 α对缺氧HCC cells的影响。使用体外和体内HCC模型来确定考克斯-2/PGE 2轴是否是HIF 2 α水平和活性的驱动因素，然后降低缺氧HCC细胞中索拉非尼治疗的敏感性。在缺氧条件下，考克斯-2/PGE 2轴通过降低von Hippel-Lindau蛋白（p-VHL）水平，有效稳定HIF 2 α并增加其水平和活性，并通过MAPK途径促进HIF 2 α核转位而增强HIF 2 α活性。HIF 2 α的激活随后导致VEGF、细胞周期蛋白D1和TGF α/EGFR通路的增强激活，以介导HCC的发展并降低索拉非尼的敏感性。更重要的是，考克斯-2特异性抑制剂协同增强了索拉非尼treatment.Conclusions的抗肿瘤活性：我们获得的数据表明，考克斯/PGE 2轴作为HIF 2 α表达和活性的调节剂，通过组成性激活TGF α/EGFR途径促进HCC的发展和降低索拉非尼的敏感性。这项研究强调了考克斯-2特异性抑制剂治疗肝癌的潜力，特别是提高索拉非尼治疗的反应。(C)2018年AACR。
Purpose: Hypoxia-inducible factor-2 alpha (HIF2 alpha) is regarded as a preferential target for individualized hepatocellular carcinoma (HCC) treatment and sorafenib resistance. Our study aimed to identify the regulatory mechanisms of HIF2 alpha activity under hypoxic conditions. We sought to determine whether the COX-2/PGE2 axis is involved in the regulatory mechanisms of HIF2 alpha activity and of sorafenib resistance in hypoxic HCC cells.Experimental Design: The cell viability, migration, and invasion abilities were measured to analyze the effects of HIF2 alpha on hypoxicHCCcells. Both in vitro and in vivo HCC models were used to determine whether the COX-2/PGE2 axis is a driver of HIF2 alpha level and activity, which then reduces the sensitivity of sorafenib treatment in hypoxic HCC cells.Results: Under hypoxic conditions, the COX-2/PGE2 axis effectively stabilized HIF2 alpha and increased its level and activity via decreasing von Hippel-Lindau protein (p-VHL) level, and also enhanced HIF2 alpha activity by promoting HIF2 alpha nuclear translocation via MAPK pathway. The activation of HIF2 alpha then led to the enhanced activation of VEGF, cyclin D1, and TGF alpha/EGFR pathway to mediate HCC development and reduce the sensitivity of sorafenib. More importantly, COX-2-specific inhibitors synergistically enhanced the antitumor activity of sorafenib treatment.Conclusions: Our data obtained demonstrate that the COX/PGE2 axis acts as a regulator of HIF2 alpha expression and activity to promote HCC development and reduce sorafenib sensitivity by constitutively activating the TGF alpha/EGFR pathway. This study highlights the potential of COX-2-specific inhibitors for HCC treatment and particularly for enhancing the response to sorafenib treatment. (C) 2018 AACR.