title: Down-regulation of suppressor of cytokine signaling 3 by miR-122 enhances interferon-mediated suppression of hepatitis B virus.
abstract: MicroRNA-122 (miR-122) is involved in the pathogenesis of several liver diseases, including chronic hepatitis B infection and hepatocellular carcinoma. This study aimed to explore the potential role of miR-122 in the interferon (IFN)-mediated suppression of hepatitis B virus (HBV) in hepatocytes. We found that elevated expression of suppressor of cytokine signaling 3 (SOCS3) following HBV infection, contributed to the inactivation of the IFN signaling pathway. Based on previous studies from our laboratory showing that miR-122 can modulate type I IFN expression by inhibiting SOCS1 expression, we analyzed the SOCS3 mRNA sequence for putative miR-122 binding sites. We demonstrate that miR-122 inhibits SOCS3 expression by targeting the 3'-untranslated region of the SOCS3 mRNA within the region 1887-1910 nucleotides. Finally, we demonstrate that significantly increased levels of IFN lead to decreased HBV expression in miR-122 mimic-treated Huh7 cells, whereas inhibition of endogenous miR-122 leads to enhanced viral production, owing to a marked decrease in IFN expression. Taken together, our results demonstrate that miR-122 down-regulates SOCS3, thus positively affecting the anti-HBV efficiency of endogenous type I IFN. Our study suggests that suppression of miR-122 induced by HBV infection, leads to the inactivation of IFN expression, which in turn enhances HBV replication, contributing to viral persistence and hepatocarcinogenesis.
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China; Laboratory of Microbiology, College of Life Science, Heilongjiang University, Harbin, China.
authors.forename: Dongni
authors.initials: D
authors.lastname: Gao
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Aixia
authors.initials: A
authors.lastname: Zhai
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qian
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Aimei
authors.initials: A
authors.lastname: Li
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Wuqi
authors.initials: W
authors.lastname: Song
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Qingmeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Kao
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China. Electronic address: fengminzhang@ems.hrbmu.edu.cn.
authors.forename: Fengmin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin 150086, Heilongjiang, China. Electronic address: zhongzh@ems.hrbmu.edu.cn.
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D020413:3' Untranslated Regions; D001665:Binding Sites; D002460:Cell Line; D015536:Down-Regulation; D006509:Hepatitis B / Q000276:immunology*; D006515:Hepatitis B virus / Q000276:immunology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D057131:Immune Evasion; D007370:Interferon Type I / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D007370:Interferon Type I; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: Hepatitis B virus; Hepatocytes; Interferon; MicroRNA-122; Suppressor of cytokine signaling 3