Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122

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• 作者：Hong-Wei Liang¹ ; ^&dagger ; ; Nan Wang¹ ; ^&dagger ; ; Yanbo Wang¹ ; ^&dagger ; ; Feng Wang² ; ^&dagger ; ; Zheng Fu¹ ; Xin Yan³ ; Hao Zhu⁴ ; Wenli Diao¹ ; Yitao Ding⁵ ; ^{yitaoding@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Xi Chen¹ ; ^{xichen@nju.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Chen-Yu Zhang¹ ; ^{cyzhang@nju.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Ke Zen¹ ; ^{kzen@nju.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：EMT ; epithelial-mesenchymal transition ; GSK-3β ; glycogen synthase kinase-3β ; HBV ; hepatitis B virus ; HBx-LINE1 ; hybrid RNA transcript of the human LINE1 and the HBV-encoded X gene ; HCC ; hepatocellular carcinoma ; HCV ; hepatitis C virus ; IGF-1R ; insulin growth factor-1 receptor ; LINEs ; long interspersed nuclear elements ; SINEs ; short interspersed nuclear elements
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：278-291
• 全文大小：2147 K

文摘

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 β-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.