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    Alcohol facilitates HCV RNA replication via up-regulation of miR-122 expression and inhibition of cyclin G1 in human hepatoma cells

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    Authors
    Hou, Wei
    Bukong, Terence N.
    Kodys, Karen
    Szabo, Gyongyi
    UMass Chan Affiliations
    Department of Medicine, Division of Gastroenterology
    Document Type
    Journal Article
    Publication Date
    2013-04-01
    Keywords
    Hepacivirus
    Ethanol
    MicroRNAs
    Cyclin G1
    Immunology of Infectious Disease
    Molecular Genetics
    Organic Chemicals
    
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    Link to Full Text
    http://dx.doi.org/10.1111/acer.12005
    Abstract
    BACKGROUND: Clinical studies demonstrate synergistic liver damage by alcohol and hepatitis C virus (HCV); however, the mechanisms by which alcohol promotes HCV infection remain obscure. The liver-specific microRNA-122 (miR-122) regulates HCV replication and expression of host genes, including Cyclin G1. Here, we hypothesized that alcohol regulates miR-122 expression and thereby modulates HCV RNA replication. METHODS: The J6/JFH/Huh-7.5 model of HCV infection was used in this study. Real-time quantitative polymerase chain reaction, Western blotting, electrophoretic mobility shift assay, and confocal microscopy were used for experimental analysis. RESULTS: We found that acute alcohol exposure (25 mM) significantly increased intracellular HCV RNA as well as miR-122 levels in Huh-7.5 and Huh-7.5/CYP2E1 expressing cells in the presence and absence of J6/JFH-HCV infection. Expression of the miR-122 target, Cyclin G1, was inhibited by alcohol both in J6/JFH-infected and uninfected Huh-7.5 cells. The use of a miR-122 inhibitor increased Cyclin G1 expression and prevented the alcohol-induced increase in HCV RNA and protein levels, suggesting a mechanistic role for alcohol-induced miR122 in HCV replication. We discovered that siRNA-mediated silencing of Cyclin G1 significantly increased intracellular HCV RNA levels compared with controls, suggesting a mechanistic role for Cyclin G1 in HCV replication. Alcohol-induced increase in miR-122 was associated with increased nuclear translocation and DNA binding of the nuclear regulatory factor-kappaB and could be prevented by NF-kappaB inhibition. CONCLUSIONS: Our novel data indicate a miR-122-mediated mechanism for alcohol increasing HCV RNA replication. We show for the first time that Cyclin G1, a miR-122 target gene, has regulatory effects on HCV replication and that alcohol increases HCV replication by regulating miR-122 and Cyclin G1.
    Source
    Alcohol Clin Exp Res. 2013 Apr;37(4):599-608. doi: 10.1111/acer.12005. Link to article on publisher's site
    DOI
    10.1111/acer.12005
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/28780
    PubMed ID
    23126531
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1111/acer.12005
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