Hepatitis B virus (HBV) causes chronic infection in about 350 million people worldwide. Given the important role of the most abundant liver-specific microRNA, miR-122, in hepatic function and liver pathology, here we investigated the potential role and mechanism of miR-122 in regulating HBV replication. We found that miR-122 expression in liver was significantly down-regulated in patients with HBV infection compared with healthy controls, and the miR-122 levels were negatively correlated with intrahepatic viral load and hepatic necroinflammation. The depletion of endogenous miR-122 by its antisense inhibitor led to enhanced HBV replication, whereas overexpression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G 1 as an miR-122 target from multiple candidate target genes that are involved in the regulation of HBV replication. Overexpression and knockdown studies both showed that cyclin G 1 regulated viral replication in HBV transfected cells. We also observed that cyclin G 1 expression was up-regulated in HBV-infected patients, and cyclin G 1 levels were inversely associated with miR-122 expression in liver tissues. Using coimmunoprecipitation, a luciferase reporter system, and electrophoretic mobility shift assay, we further demonstrated that cyclin G 1 specifically interacted with p53, and this interaction blocked the specific binding of p53 to HBV enhancer elements and simultaneously abrogated p53-mediated inhibition of HBV transcription. Finally, we show that miR-122 suppressed HBV replication in p53 wildtype cells but not in null isogenic cells. Conclusion: miR-122 down-regulates its target cyclin G 1, and thus interrupts the interaction between cyclin G 1 and p53 and abrogates p53-mediated inhibition of HBV replication. Our work shows that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis. (HEPATOLOGY 2012;) © 2011 American Association for the Study of Liver Diseases.
CITATION STYLE
Wang, S., Qiu, L., Yan, X., Jin, W., Wang, Y., Chen, L., … Meng, S. (2012). Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G 1-modulated P53 activity. Hepatology, 55(3), 730–741. https://doi.org/10.1002/hep.24809
Mendeley helps you to discover research relevant for your work.