Loss of microRNA 122 expression in patients with hepatitis B enhances hepatitis B virus replication through cyclin G1-modulated P53 activity

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, PR China.
Hepatology (Impact Factor: 11.06). 03/2012; 55(3):730-41. DOI: 10.1002/hep.24809
Source: PubMed


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.

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    • "p53 can bind to HBV enhancer elements and act as a suppressor of HBV replication 37. The inhibitory effect of p53 on HBV replication is protected by miR-122, which prevents cyclin G1 from interacting with p53 and blocking its specific binding to HBV enhancer elements 38. However, heme oxygenase-1 (HO-1), an anti-HBV enzyme, is simultaneously targeted by miR-122; thus, miR-122 may also promote HBV infection by repressing HO-1-mediated antiviral activity 39. "
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    ABSTRACT: Hepatitis B virus (HBV) infection is a global problem and a major risk factor for hepatocellular carcinoma (HCC). microRNAs (miRNAs) comprise a group of small noncoding RNAs regulating gene expression at the posttranslational level, thereby participating in fundamental biological processes, including cell proliferation, differentiation, and apoptosis. In this review, we summarize the roles of miRNAs in HBV infection, the recently identified mechanism underlying dysregulation of miRNAs in HBV-associated HCC, and their association with hepatocarcinogenesis. Moreover, we discuss the recent advances in the use of circulating miRNAs in the early diagnosis of HCC as well as therapies based on these aberrantly expressed miRNAs.
    Preview · Article · Sep 2014 · Theranostics
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    • "As a proto-oncogene, cyclin G1 is closely related to cancer [[52]]. Cyclin G1 is over-expressed in HBV-infected liver cells, where decreased expression of miRNA-122 is frequently found [[51]]. Excessive cyclin G1 in association with PP2A B subunits promotes the dephosphorylation of Mdm-2, which is a repressor protein of p53. "
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    ABSTRACT: The pathogenesis of hepatocellular carcinoma (HCC) is not fully understood, which has affected the early diagnosis and treatment of HCC and the survival time of patients. MicroRNAs (miRNAs) are a class of evolutionarily conserved small, non-coding RNAs, which regulate the expression of various genes post-transcriptionally. Emerging evidence indicates that the key enzymes involved in the miRNA biosynthesis pathway and some tumor-specific miRNAs are widely deregulated or upregulated in HCC and closely associated with the occurrence and development of various cancers, including HCC. Early studies have shown that miRNAs have critical roles in HCC progression by targeting many critical protein-coding genes, thereby contributing to the promotion of cell proliferation; the avoidance of apoptosis, inducing via angiogenesis; and the activation of invasion and metastasis pathways. Experimental data indicate that discovery of increasing numbers of aberrantly expressed miRNAs has opened up a new field for investigating the molecular mechanism of HCC progression. In this review, we describe the current knowledge about the roles and validated targets of miRNAs in the above pathways that are known to be hallmarks of HCC, and we also describe the influence of genetic variations in miRNA biosynthesis and genes.
    Full-text · Article · Jul 2014 · Cell Communication and Signaling
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    • "Further, up-regulation of PBF may contribute to HBV infection-related hepatocellular carcinoma (HCC) because PBF interacts with PTTG1 and increases its transcriptional activity at multiple oncogenes (Li et al., 2013), as well as promotes cell proliferation , invasion, and HCC tumor growth in mice. Under HBV infection, the HBV RNA copy number per cell reaches up to 105 (Li et al., 2013; Wang et al., 2012), and miR-122 is expressed in hepatocytes at 50,000 copies per cell (Hu et al., 2012; Filipowicz and Grosshans, 2011). Conceivably, a positive cross-regulation between HBV RNAs and cyclin G1 or PBF occurs in the presence of the large amounts of viral RNAs which efficiently sequester miR-122, resulting in intermediate miR-122 levels in hepatocytes. "
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    ABSTRACT: During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns (PAMPs) in innate immunity. Here, considering recent research progress in microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs), we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed "competitive viral and host RNAs" (cvhRNAs). We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus (HBV), as well as Herpesvirus saimiri (HVS), lytic murine cytomegalovirus (MCMV) and human cytomegalovirus (HCMV) infections. In addition, the cvhRNA hypothesis also predicts possible cross-regulation between host and other viruses, such as hepatitis C virus (HCV), HIV, influenza virus, human papillomaviruses (HPV). Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.
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