近日,国际杂志Hepatology在线刊登了中科院微生物研究所研究人员的最新研究进展“Loss of MiR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1 modulated P53 activity,”,文章中,作者揭示了乙肝感染慢性化机制的相关研究。
doi:10.1002/hep.24809
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Loss of MiR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1 modulated P53 activity
Saifeng Wang1,†, Lipeng Qiu1,†, Xiaoli Yan1, Wensong Jin1, Yanzhong Wang1, Lizhao Chen1, Erjie Wu1, Xin Ye1, George F Gao1, Fusheng Wang2, Yu Chen3, Zhongping Duan3,*,‡, Songdong Meng1,*
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 over-expression of miR-122 by transfection of mimic or its expression vector inhibited viral production. We next identified cyclin G1 as a miR-122 target from multiple candidate target genes which is involved in the regulation of HBV replication. Over-expression and knock-down studies both showed that cyclin G1 regulated viral replication in HBV transfected cells. We also observed that cyclin G1 expression was up-regulated in HBV infected patients, and cyclin G1 levels were inversely associated with miR-122 expression in liver tissues. Using co-immunoprecipitation, luciferase reporter system and electrophoretic mobility shift assay (EMSA), we further demonstrated that cyclin G1 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 showed miR-122 suppressed HBV replication in p53 wild-type cells but not in null isogenic cells. Conclusion: miR-122 down-regulates its target cyclin G1, thus interrupts interaction between cyclin G1 and p53, and abrogates p53-mediated inhibition of HBV replication. Our work showed that miR-122 down-regulation induced by HBV infection can impact HBV replication and possibly contribute to viral persistence and carcinogenesis. 作者: bubu169 时间: 2012-2-22 08:24