ETS-1 induces Sorafenib-resistance in hepatocellular carcinoma cells via regulating transcription factor activity of PXR
ETS-1 induces Sorafenib-resistance in hepatocellular carcinoma cells via regulating transcription factor activity of PXR
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ETS-1通过调节PXR转录因子活性诱导肝细胞癌细胞对索拉非尼耐药
DOI：
10.1016/j.phrs.2018.08.003
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发表时间：
2018-09-01
影响因子：
9.3
通讯作者：
Guo, Yingjie
中科院分区：
文献类型：
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作者：
Shao, Zhiyi;Li, Yibo;Guo, Yingjie
转录因子E26转化特异性序列1（ETS-1）是人类癌细胞，尤其是肝细胞癌（HCC）细胞转移的主要调控因子，它的表达将影响接受化疗的HCC患者的预后。然而，ETS-1在肝癌细胞对分子靶向药物耐药中的调节作用仍然知之甚少。在目前的工作中，我们证明ETS-1高表达与接受索拉非尼治疗的晚期肝癌患者预后不良相关。在机制上，ETS-1直接与核孕烷X受体（PXR）结合，增强PXR的转录因子活性，从而进一步导致PXR下游多药耐药相关基因的诱导。ETS-1的过表达加速了索拉非尼在HCC细胞中的代谢清除，并导致这些细胞更好的存活和更快的迁移。治疗研究表明，ETS-1促进肝癌模型对索拉非尼的耐药性，ETS-1阻断剂通过降低PXR活化增强索拉非尼的抗肿瘤能力。因此，我们的研究表明，ETS-1可以增强PXR的激活，并成为克服肝癌治疗中索拉非尼耐药的潜在治疗靶点。
Transcription factor E26 transformation specific sequence 1 (ETS-1) is a primary regulator in the metastasis of human cancer cells, especially hepatocellular carcinoma (HCC) cells; and it would affect the prognosis of HCC patients who received chemotherapies. However, the regulatory role of ETS-1 in the resistance of HCC cells to molecular-targeting agent remains poorly understood. In the present work, we demonstrate that high ETS-1 expression correlates with poor prognosis of advanced HCC patients received Sorafenib treatment. Mechanistically, ETS-1 binds to nuclear Pregnane X receptor (PXR) directly and enhances PXR's transcription factor activity, which further leads to the induction of the PXR's downstream multi-drug resistance related genes. Overexpression of ETS-1 accelerates the metabolic clearance of Sorafenib in HCC cells and leads to the better survival and faster migration of those cells. The therapeutic studies show that ETS-1 promotes the Sorafenib-resistance of HCC tumor models and ETS-1 blockade enhances the anti-tumor capacity of Sorafenib by decreasing PXR activation. Thus, our study suggests that ETS-1 could enhance the activation of PXR and be a potential therapeutic target for overcoming Sorafenib resistance in HCC treatment.