Kim Ji Hyun, Lee Chang Ho, Lee Seong-Wook
Department of Integrated Life Sciences, Research Institute of Advanced Omics, Dankook University, 152, Jukjeon-ro, Suji-gu, Yongin 16890, Republic of Korea; Department of Molecular Biology, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan 31116, Republic of Korea.
Department of Integrated Life Sciences, Research Institute of Advanced Omics, Dankook University, 152, Jukjeon-ro, Suji-gu, Yongin 16890, Republic of Korea.
Mol Ther Nucleic Acids. 2019 Mar 1;14:483-497. doi: 10.1016/j.omtn.2019.01.006. Epub 2019 Jan 18.
The mechanism by which hepatitis C virus (HCV) causes fibrosis and other chronic liver diseases remains poorly understood. Previously, we observed that HCV infection induces microRNA-192 (miR-192) expression, which in turn upregulates transforming growth factor β1 (TGF-β1) in hepatocytes. In this study, we aimed to determine the roles and mechanisms of HCV-induced miR-192 expression during chronic liver injury and fibrosis and to identify potential target of the liver disease. Noticeably, miR-192 is secreted and transmitted through exosomes from HCV-replicating hepatocytes into hepatic stellate cells (HSCs). Exosomal transferred miR-192 upregulated fibrogenic markers in HSCs through TGF-β1 upregulation, resulting in the activation and transdifferentiation of HSCs into myofibroblasts. Anti-miR-192 treatment of HCV-replicating hepatocytes efficiently reduced miR-192 levels in exosomes, downregulated miR-192 and fibrogenic marker levels in HSCs, and impeded transdifferentiation of the cells. In contrast, miR-192 mimic RNA treatment significantly increased miR-192 levels in exosomes from naive hepatocytes, increased miR-192 and fibrogenic marker expression in HSCs, and induced transdifferentiation of the cells. Notably, transdifferentiation of exosome-exposed HSCs was reversed following treatment with anti-miR-192 into the HSCs. This study revealed a novel mechanism of HCV-induced liver fibrosis and identified exosomal miR-192 as a major regulator and potential treatment target for HCV-mediated hepatic fibrosis.
丙型肝炎病毒（HCV）导致肝纤维化和其他慢性肝病的机制仍知之甚少。此前，我们观察到HCV感染可诱导微小RNA-192（miR-192）表达，进而上调肝细胞中的转化生长因子β1（TGF-β1）。在本研究中，我们旨在确定HCV诱导的miR-192表达在慢性肝损伤和纤维化过程中的作用及机制，并确定该肝病的潜在靶点。值得注意的是，miR-192通过外泌体从HCV复制的肝细胞分泌并传递至肝星状细胞（HSCs）。外泌体转移的miR-192通过上调TGF-β1上调HSCs中的纤维化标志物，导致HSCs激活并转分化为肌成纤维细胞。用抗miR-192处理HCV复制的肝细胞可有效降低外泌体中的miR-192水平，下调HSCs中的miR-192和纤维化标志物水平，并阻碍细胞的转分化。相反，miR-192模拟RNA处理显著增加了来自未感染肝细胞的外泌体中的miR-192水平，增加了HSCs中miR-192和纤维化标志物的表达，并诱导细胞转分化。值得注意的是，在用抗miR-192处理后，暴露于外泌体的HSCs的转分化被逆转回HSCs。本研究揭示了HCV诱导肝纤维化的新机制，并确定外泌体miR-192是HCV介导的肝纤维化的主要调节因子和潜在治疗靶点。
