Regulation of hepatitis C virus by microRNA-122: Figure 1

Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, UK.
Biochemical Society Transactions (Impact Factor: 3.19). 01/2009; 36(Pt 6):1220-3. DOI: 10.1042/BST0361220
Source: PubMed


Most metazoan miRNAs (microRNAs) bind to sites in the 3'-UTRs (untranslated regions) of mRNA targets and negatively regulate protein synthesis. The liver-specific miR-122, however, exerts a positive effect on HCV (hepatitis C virus) RNA levels by binding directly to a site in the 5'-UTR of the viral RNA. HCV translation and RNA stability are unaffected, and therefore miR-122 is likely to act at the level of viral replication. The miR-122-binding site in HCV RNA was examined to determine whether the nature of the site is responsible for the unusual mode of action for a miRNA. When the site was placed in the 3'-UTR of a reporter mRNA, miR-122 repressed translation, and therefore the location of the miR-122-binding site dictates its effect on gene expression. Additionally, a second binding site for miR-122 was identified in the HCV 5'-UTR, and miR-122 binding to both sites in the same viral RNA was found to be necessary for viral replication. The two sites are adjacent and are separated by a short spacer, which is largely conserved between HCV genotypes. The binding site requirements for miR-122 to positively regulate HCV replication provide an insight into this unusual mode of miRNA action.

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    • "Furthermore, restoration of miR-122 expression was found to prevent development of liver disease and HCC in mouse models, supporting its tumor-suppressive role [Nassirpour et al., 2013]. However, interestingly, miR-122 has also been shown to play an important role in the life cycle of hepatitis C virus (HCV) and to be an essential host factor for HCV infection [Jopling, 2008; Roberts et al., 2011]. Accordingly, treatment of chronically infected nonhuman primates with a locked nucleic acid (LNA)–modified antisense oligonucleotide complementary to the miR-122 sequence led to a long-lasting suppression of HCV viremia, suggesting that miR-122 represents a potential target for antiviral therapies [Lanford et al., 2010]. "
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    ABSTRACT: Preclinical Research Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment. Drug Dev Res, 2015. © 2015 Wiley Periodicals, Inc.
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    • "On the other hand, other miRNAs can also up-regulate HCV replication where, high expression of miR-122 in the liver, which interacts with the 5 UTR of the viral genome, promotes viral replication in hepatic cells (Jopling et al., 2006; Jopling et al., 2005). Indeed, the expression of miRNA-122 in liver cells is required for viral viability (Jopling, 2008). The gene expression regulation carried out by miRNAs can be mediated by their interaction with RNA sequences present in viral genomes as well as in cellular mRNAs, modulating host factors involved in mechanisms of antiviral response. "
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    • "MicroRNAs (miRNAs) are small (21–23 nt) noncoding RNA molecules that canonically function by binding to partially complementary sites in the 3′UTR of mRNA targets, leading to translational repression and mRNA degradation (6). In contrast, miR-122 regulates HCV by interacting with two adjacent sites in the viral 5′UTR, immediately upstream of the IRES, and positively regulating the viral replication cycle (3,7). "
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    ABSTRACT: The P body protein LSm1 stimulates translation and replication of hepatitis C virus (HCV). As the liver-specific microRNA-122 (miR-122) is required for HCV replication and is associated with P bodies, we investigated whether regulation of HCV by LSm1 involves miR-122. Here, we demonstrate that LSm1 contributes to activation of HCV internal ribosome entry site (IRES)-driven translation by miR-122. This role for LSm1 is specialized for miR-122 translation activation, as LSm1 depletion does not affect the repressive function of miR-122 at 3' untranslated region (UTR) sites, or miR-122-mediated cleavage at a perfectly complementary site. We find that LSm1 does not influence recruitment of the microRNA (miRNA)-induced silencing complex to the HCV 5'UTR, implying that it regulates miR-122 function subsequent to target binding. In contrast to the interplay between miR-122 and LSm1 in translation, we find that LSm1 is not required for miR-122 to stimulate HCV replication, suggesting that miR-122 regulation of HCV translation and replication have different requirements. For the first time, we have identified a protein factor that specifically contributes to activation of HCV IRES-driven translation by miR-122, but not to other activities of the miRNA. Our results enhance understanding of the mechanisms by which miR-122 and LSm1 regulate HCV.
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