来自中科院微生物研究所病原微生物与免疫学院重点实验室的研究人员发表了题为“Loss of MiR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1 modulated P53 activity”的文章,发现了一种小分子RNA:miR-122在乙肝病毒复制,以及持续感染途经中的新调控作用,这为进一步了解HBV病毒的持续感染机制和肝癌发生途径提供了新的依据和阐释,同时提出miR-122作为治疗慢性乙肝的潜在新一代药物的可行性。相关成果公布在Hepatology杂志上。
领导这一研究的是微生物研究所孟颂东研究员,孟颂东研究员2007年入选中科院“百人计划”,主要研究方向为病毒与肿瘤免疫。研究热休克蛋白在抗乙型肝炎病毒感染和肿瘤免疫中的调控机制,相关治疗性疫苗的研发;非编码RNA对乙肝病毒复制作用,对T细胞功能的调节作用。
全世界有3.5亿人慢性感染乙肝病毒(HBV),在我国感染人群约9300万,乙肝慢性引起急、慢性病毒性肝炎,与肝纤维化、肝癌的发生发展密切相关,严重威胁人类的健康。病毒感染人体后,病毒与宿主之间的相互作用决定感染的结局和疾病转归。然而,迄今为止,病毒逃逸宿主防御及乙肝慢性化机制并不清楚。因此,研究病毒与宿主因子相互作用及病毒持续感染的分子机制,将有助于设计治疗慢性乙肝的新的靶向药物。
microRNA-122 (miR-122)在肝脏中特异性表达,而且是肝细胞中丰度最高的小RNA,在肝脏功能和病理中发挥重要作用。在这篇文章中,研究人员发现,miR- 122作为宿主限制性因子明显抑制病毒复制,而在乙肝慢性感染中由于慢性炎症和病毒感染引起miR-122下调。进一步研究查明,miR-122通过 cyclin G1/p53通路对病毒复制起调控作用。
基于以上研究,研究人员提出乙肝感染慢性化的新机制:乙肝慢性感染下调宿主限制性小RNA,通过miR-122-cyclin G1/p53-病毒增强子通路促进病毒的表达与复制。这为进一步了解HBV病毒的持续感染机制和肝癌发生途径提供了新的依据和阐释,同时提出miR- 122作为治疗慢性乙肝的潜在新一代药物的可行性。
除此之外,孟颂东研究组去年还获得了热休克蛋白gp96抗乙肝病毒方面的系列进展。他们在前期研究中发现调节性T细胞(Treg)对gp96免疫活性起负调控作用,之后进一步查明清除Treg可显著提高gp96的T细胞免疫活性和抗肿瘤活性,为提高gp96疫苗的免疫活性以及目前gp96作为肿瘤自体疫苗在临床中治疗肿瘤提供理论指导;通过乙肝病毒(HBV)转基因鼠模型,发现gp96介导的T细胞免疫应答可有效抑制和清除乙肝病毒,gp96佐剂疫苗能有效激活HBV特异性T细胞,并降低转基因鼠Treg的数量。
原文摘要:
Loss of MiR-122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1 modulated P53 activity.
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. (HEPATOLOGY 2011.).
作者简介:
孟颂东 博士 研究员,中科院“百人计划”入选者
1998 年博士毕业于中科院沈阳应用生态所,毕业后在中科院微生物所分子病毒室做博士后,2002-2007年在美国西南医学中心肿瘤免疫中心做博士后,2007 年入选中科院“百人计划”,在微生物所病原微生物与免疫学院重点实验室工作。先后在Lancet、PNAS、Clinical Cancer Research、European Journal of Immunology等发表论文十余篇。
研究方向:病毒与肿瘤免疫。研究热休克蛋白在抗乙型肝炎病毒感染和肿瘤免疫中的调控机制,相关治疗性疫苗的研发;非编码RNA对乙肝病毒复制作用,对T细胞功能的调节作用。
承担课题:承担863项目、“973”子项目和自然基金项目等。
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