Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events
Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events
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DOI：
10.1038/onc.2012.484
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发表时间：
2013-09-26
期刊：
影响因子：
8
通讯作者：
Pawlotsky, J-M
中科院分区：
文献类型：
--
作者：
Higgs, M. R.;Lerat, H.;Pawlotsky, J-M
丙型肝炎病毒（HCV）的慢性感染是肝细胞癌（HCC）发生和发展的主要危险因素，尽管其潜在机制尚不清楚。c-Myc癌基因部分通过诱导遗传损伤和抑制细胞对遗传毒性应激的反应而促成许多类型的癌症（包括HCC）的发生。在这里，我们显示了一个以前未发现的机制之间的联系HCV感染和增强c-Myc表达。c-Myc的表达在非肿瘤肝组织中增强，这些组织来自有或没有HCC的HCV感染个体，并且在携带HCV复制子和感染性HCV株JFH 1的肝细胞系中增强。在表达整个HCV开放阅读框的转基因鼠模型中，体内证实了c-Myc表达的增加，证明了HCV蛋白表达在c-Myc诱导中的直接作用。从机制上讲，Akt被HCV非结构蛋白NS 5A激活，以及随后转录因子β-连环蛋白的稳定化，被证明是c-Myc启动子激活和c-Myc转录增加的原因。在这种情况下，β-连环蛋白依赖性c-Myc表达导致活性氧产生增加、线粒体扰动、DNA损伤增强和异常细胞周期停滞。总之，这些数据为HCV相关HCC的机制提供了新的见解，强烈表明c-Myc在此过程中起着至关重要的作用。
Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of hepatocellular carcinoma (HCC), although the underlying mechanisms are unclear. The c-Myc oncogene contributes to the genesis of many types of cancers, including HCC, partly via the induction of genetic damage and the inhibition of the cellular response to genotoxic stress. Here, we show a previously undiscovered mechanistic link between HCV infection and enhanced c-Myc expression. c-Myc expression was augmented in non-tumoral liver tissues from HCV-infected individuals with or without HCC and in hepatocyte cell lines harboring an HCV replicon and the infectious HCV strain JFH1. Increased c-Myc expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame, demonstrating a direct role for HCV protein expression in c-Myc induction. Mechanistically, activation of Akt by the HCV non-structural protein NS5A, and the subsequent stabilization of the transcription factor beta-catenin, was demonstrated to be responsible for activation of the c-Myc promoter, and for increased c-Myc transcription. beta-Catenin-dependent c-Myc expression in this context led to increased production of reactive oxygen species, mitochondrial perturbation, enhanced DNA damage and aberrant cell-cycle arrest. Together, these data provide a novel insight into the mechanisms involved in HCV-associated HCCs, strongly suggesting that c-Myc has a crucial contributory role in this process.