From the Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, New Jersey 07103.
the Department of Biochemistry, Faculty of Pharmacy, Cumhuriyet University, Sivas, Turkey 58140.
J Biol Chem. 2017 Dec 29;292(52):21676-21689. doi: 10.1074/jbc.M117.792721. Epub 2017 Oct 27.
Hepatitis C virus (HCV) infection is a major risk factor for the development of chronic liver disease. The disease typically progresses from chronic HCV to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and death. Chronic inflammation associated with HCV infection is implicated in cirrhosis and HCC, but the molecular players and signaling pathways contributing to these processes remain largely unknown. Interferon regulatory factor 5 (IRF5) is a molecule of interest in HCV-associated HCC because it has critical roles in virus-, Toll-like receptor (TLR)-, and IFN-induced signaling pathways. IRF5 is also a tumor suppressor, and its expression is dysregulated in several human cancers. Here, we present first evidence that IRF5 expression and signaling are modulated during HCV infection. Using HCV infection of human hepatocytes and cells with autonomously replicating HCV RNA, we found that levels of IRF5 mRNA and protein expression were down-regulated. Of note, reporter assays indicated that IRF5 re-expression inhibited HCV protein translation and RNA replication. Gene expression analysis revealed significant differences in the expression of cancer pathway mediators and autophagy proteins rather than in cytokines between IRF5- and empty vector-transfected HCV replicon cells. IRF5 re-expression induced apoptosis via loss in mitochondrial membrane potential, down-regulated autophagy, and inhibited hepatocyte cell migration/invasion. Analysis of clinical HCC specimens supports a pathologic role for IRF5 in HCV-induced HCC, as IRF5 expression was down-regulated in livers from HCV-positive HCV-negative HCC patients or healthy donor livers. These results identify IRF5 as an important suppressor of HCV replication and HCC pathogenesis.
丙型肝炎病毒（HCV）感染是慢性肝病发展的主要危险因素。该疾病通常从慢性 HCV 发展为纤维化、肝硬化、肝细胞癌（HCC）和死亡。与 HCV 感染相关的慢性炎症与肝硬化和 HCC 有关，但导致这些过程的分子参与者和信号通路在很大程度上仍不清楚。干扰素调节因子 5（IRF5）是与 HCV 相关 HCC 中感兴趣的分子，因为它在病毒、Toll 样受体（TLR）和 IFN 诱导的信号通路中具有关键作用。IRF5 也是一种肿瘤抑制因子，其表达在几种人类癌症中失调。在这里，我们首次提供了证据表明 IRF5 的表达和信号在 HCV 感染过程中受到调节。使用 HCV 感染人肝细胞和具有自主复制 HCV RNA 的细胞，我们发现 IRF5 mRNA 和蛋白表达水平下调。值得注意的是，报告基因分析表明，IRF5 的重新表达抑制了 HCV 蛋白翻译和 RNA 复制。基因表达分析显示，IRF5 和空载体转染的 HCV 复制子细胞之间在癌症途径介质和自噬蛋白的表达而非细胞因子方面存在显著差异。IRF5 的重新表达通过线粒体膜电位丧失诱导细胞凋亡，下调自噬，并抑制肝细胞的迁移/侵袭。对临床 HCC 标本的分析支持 IRF5 在 HCV 诱导的 HCC 中的病理作用，因为 HCV 阳性 HCC 患者或健康供体肝脏中的 IRF5 表达下调。这些结果表明 IRF5 是 HCV 复制和 HCC 发病机制的重要抑制剂。
