title: Silencing of microRNA-122 enhances interferon-α signaling in the liver through regulating SOCS3 promoter methylation.
abstract: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. Although novel drugs against HCV are under development, the current standard therapy consists principally of interferon (IFN). To improve the response to IFN treatment by enhancing interferon-stimulated response element (ISRE)-mediated gene transcription, we screened 75 microRNAs highly expressed in hepatocytes for their ability to modulate ISRE activity. Overexpression of microRNA-122 (miR122) significantly suppressed ISRE activity. Conversely, silencing of miR122 function enhanced IFN-induced ISRE activity, by decreasing expression of suppressor of cytokine signaling 3 (SOCS3). This decrease in SOCS3 level was not mediated by microRNA target gene suppression, but rather by enhanced methylation at SOCS3 gene promoter. Taken together, our data, along with the fact that antisense oligonucleotides of miR122 also directly inhibit HCV replication, suggest that a combination therapy comprising IFN and silencing of miR122 function may be a promising therapeutic option in the near future.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Akemi
authors.initials: A
authors.lastname: Takata
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kishikawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kojima
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015870:Gene Expression; D020868:Gene Silencing; D019698:Hepatitis C, Chronic / Q000628:therapy; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C531907:MIRN122 microRNA, human; C574934:MIRN885 microRNA, human; D035683:MicroRNAs; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins