近日,，國際雜志Hepatology在線刊登了中科院微生物研究所研究人員的最新研究進展“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機制的相關(guān)研究,。
全世界有3.5億人慢性感染乙肝病毒（HBV），在我國感染人群約9300萬,，乙肝慢性引起急,、慢性病毒性肝炎，與肝纖維化,、肝癌的發(fā)生發(fā)展密切相關(guān),，嚴重威脅人類的健康。病毒感染人體后,，病毒與宿主之間的相互作用決定感染的結(jié)局和疾病轉(zhuǎn)歸,。然而，迄今為止,，病毒逃逸宿主防御及乙肝慢性化機制并不清楚,。因此,，研究病毒與宿主因子相互作用及病毒持續(xù)感染的分子機制，將有助于設(shè)計治療慢性乙肝的新的靶向藥物,。
microRNA-122 (miR-122)在肝臟中特異性表達,，而且是肝細胞中豐度最高的小RNA，在肝臟功能和病理中發(fā)揮重要作用,。在“973”,、國家自然基金等項目的資助下，中科院微生物研究所孟頌東研究員課題組新近的研究發(fā)現(xiàn),，miR-122作為宿主限制性因子明顯抑制病毒復(fù)制,，而在乙肝慢性感染中由于慢性炎癥和病毒感染引起miR-122下調(diào)。進一步研究查明,，miR-122通過cyclin G1/p53通路對病毒復(fù)制起調(diào)控作用,。
基于以上研究，課題組提出乙肝感染慢性化的新機制：乙肝慢性感染下調(diào)宿主限制性小RNA,，通過miR-122-cyclin G1/p53-病毒增強子通路促進病毒的表達與復(fù)制,。這為進一步了解HBV病毒的持續(xù)感染機制和肝癌發(fā)生途徑提供了新的依據(jù)和闡釋，同時提出miR-122作為治療慢性乙肝的潛在新一代藥物的可行性,。（生物谷Bioon.com）
doi:10.1002/hep.24809
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PMID:
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.
