Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122
Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122
复制标题
乙型肝炎病毒-人嵌合转录本HBx-LINE1通过隔离细胞microRNA-122促进肝损伤
DOI：
10.1016/j.jhep.2015.09.013
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发表时间：
2016-02-01
影响因子：
25.7
通讯作者：
Zen, Ke
中科院分区：
文献类型：
--
作者：
Liang, Hong-Wei;Wang, Nan;Zen, Ke
背景和目标：慢性B型肝炎病毒（HBV）携带者具有发生肝细胞癌（HCC）的高风险，但其潜在机制尚不清楚。最近的研究表明，病毒-人杂合RNA转录物在促进HCC进展中起关键作用，可能是负责HBV感染患者中HCC发展的分子。在这里，我们确定HBx-LINE 1（人LINE 1和HBV阳性HCC肿瘤细胞中产生的HBV编码的X基因的杂合RNA转录物）是否可以作为分子海绵用于隔离miR-122并促进肝细胞异常有丝分裂和小鼠肝损伤。方法：配对的肿瘤和远端正常肝组织标本，以及HBx-LINE 1过表达肝细胞，检测HBx-LINE 1与miR-122之间的关系。通过qRT-PCR和北方印迹分析HBx-LINE 1和miR-122的水平。通过荧光素酶报告基因测定分析HBx-LINE 1-miR-122结合。通过组织染色和血清天冬氨酸转氨酶、丙氨酸转氨酶和总胆红素测量来监测小鼠肝损伤。每个HBx-LINE 1由6个miR-122结合位点组成，并且HBx-LINE 1的强制表达有效地耗尽细胞miR-122，促进肝细胞上皮-间质转化（EMT）样变化，包括β-连环蛋白信号传导激活、E-钙粘蛋白减少和细胞迁移增强。给予HBx-LINE 1的小鼠显示出显著的小鼠肝细胞异常有丝分裂和肝损伤。结论：miR-122阻断HBx-LINE 1的作用可能是促进肝细胞EMT样改变和小鼠肝损伤的机制之一。(C)2015年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Chronic hepatitis B virus (HBV) carriers have a high risk to develop hepatocellular carcinoma (HCC) but the underlying mechanism remains unclear. Recent studies suggest that viral-human hybrid RNA transcripts, which play a critical role in promoting HCC progression, may be the molecules responsible for the development of HCC in HBV infected patients. Here we determine whether HBx-LINE1, a hybrid RNA transcript of the human LINE1 and the HBV-encoded X gene generated in tumor cells of HBV-positive HCC, can serve as a molecular sponge for sequestering miR-122 and promoting liver cell abnormal mitosis and mouse hepatic injury.Methods: Paired tumor and distal normal liver tissue specimens, as well as HBx-LINE1 overexpressing hepatic cells, were used to test the relationship between HBx-LINE1 and miR-122. Levels of HBx-LINE1 and miR-122 were assayed by qRT-PCR and Northern blot. HBx-LINE1-miR-122 binding was analyzed by luciferase reporter assay. Mouse hepatic injury was monitored by tissue staining and serum aspartate transaminase, alanine aminotransferase and total bilirubin measurement.Results: HBx-LINE1 in HBV-positive HCC tissues was inversely correlated with miR-122. Each HBx-LINE1 consists of six miR-122-binding sites, and forced expression of HBx-LINE1 effectively depleted cellular miR-122, promoting hepatic cell epithelial-mesenchymal transition (EMT)-like changes, including beta-catenin signaling activation, E-cadherin reduction and cell migration enhancement. Mice administered with HBx-LINE1 display a significant mouse liver cell abnormal mitosis and hepatic injury. However, all these effects of HBx-LINE1 are completely abolished by miR-122.Conclusions: Our finding illustrates a previously uncharacterized miR-122-sequestering mechanism by which HBx-LINE1 promotes hepatic cell EMT-like changes and mouse liver injury. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.