Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.
Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.
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DOI：
10.1038/s41419-022-05022-1
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发表时间：
2022-07-04
影响因子：
9
通讯作者：
Rana, Basabi
中科院分区：
文献类型：
--
作者：
Vishnoi, Kanchan;Ke, Rong;Viswakarma, Navin;Srivastava, Piush;Kumar, Sandeep;Das, Subhasis;Singh, Sunil Kumar;Principe, Daniel R.;Rana, Ajay;Rana, Basabi
肝细胞癌（HCC）的发病率和死亡率在包括美国在内的西方国家呈上升趋势，主要原因是发现晚。近十年来，索拉非尼一直是fda批准的治疗晚期不可切除HCC的一线药物，但由于耐药的发展，其疗效有限。最近，其他几种多激酶抑制剂（lenvatinib, cabozantinib, regorafenib），人单克隆抗体（ramucirumab）和免疫检查点抑制剂（nivolumab, pembrolizumab）已被批准作为全身治疗。尽管如此，患者的中位生存期并没有明显增加。了解控制HCC耐药的分子机制对于提高现有药物的疗效和未来开发更有效的药物至关重要。我们使用转录因子RT2 Profiler PCR阵列对索拉非尼耐药（sorafenib-resistant, soraR） HCC细胞进行的研究显示，所有soraR细胞中E26转化特异性-1 （Ets-1）转录因子均增加。HCC TMA研究显示，与正常肝脏相比，晚期HCC中Ets-1表达增加。过表达或敲低Ets-1可调节索拉非尼耐药相关上皮-间质转化（EMT）、迁移和细胞存活。此外，soraR细胞显示出线粒体损伤和线粒体活性氧（mROS）产生的显著减少，这是通过敲低Ets-1表达而拮抗的。更深入的分析发现GPX-2是Ets-1诱导索拉非尼耐药的下游介质，Ets-1敲低可下调其耐药水平，而其他抗氧化途径基因不受影响。有趣的是，抑制GPX2表达显著增加sorafenib在soraR细胞中的敏感性。我们的研究表明，在soraR细胞中激活一种新的Ets-1-GPX2信号轴，靶向它可能成功地拮抗耐药并提高疗效。
The incidence and mortality of hepatocellular carcinoma (HCC) are on a rise in the Western countries including US, attributed mostly to late detection. Sorafenib has been the first-line FDA-approved drug for advanced unresectable HCC for almost a decade, but with limited efficacy due to the development of resistance. More recently, several other multi-kinase inhibitors (lenvatinib, cabozantinib, regorafenib), human monoclonal antibody (ramucirumab), and immune checkpoint inhibitors (nivolumab, pembrolizumab) have been approved as systemic therapies. Despite this, the median survival of patients is not significantly increased. Understanding of the molecular mechanism(s) that govern HCC resistance is critically needed to increase efficacy of current drugs and to develop more efficacious ones in the future. Our studies with sorafenib-resistant (soraR) HCC cells using transcription factor RT2 Profiler PCR Arrays revealed an increase in E26 transformation–specific-1 (Ets-1) transcription factor in all soraR cells. HCC TMA studies showed an increase in Ets-1 expression in advanced HCC compared to the normal livers. Overexpression or knocking down Ets-1 modulated sorafenib resistance-related epithelial–mesenchymal transition (EMT), migration, and cell survival. In addition, the soraR cells showed a significant reduction of mitochondrial damage and mitochondrial reactive oxygen species (mROS) generation, which were antagonized by knocking down Ets-1 expression. More in-depth analysis identified GPX-2 as a downstream mediator of Ets-1-induced sorafenib resistance, which was down-regulated by Ets-1 knockdown while other antioxidant pathway genes were not affected. Interestingly, knocking down GPX2 expression significantly increased sorafenib sensitivity in the soraR cells. Our studies indicate the activation of a novel Ets-1–GPX2 signaling axis in soraR cells, targeting which might successfully antagonize resistance and increase efficacy.
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Karpel-Massler G;Banu MA;Shu C;Halatsch ME;Westhoff MA;Bruce JN;Canoll P;Siegelin MD
通讯作者：
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