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Regulation of interferon signaling and HCVRNA replication by extracellular matrix

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Although interferon (IFN)based treatment of patients with chronic hepatitis C virus (HCV) infection is widely applied, treatment resistance is often observed in patients with advanced liver fibrosis. Given that the molecular mechanisms of IFN resistance in liver fibrosis remain elusive, the present study investigated the effects of extracellular matrix (ECM) on IFN signaling in hepatic cells. The native HuH7 human hepatoma cell line and HuH7 cells were stably transfected with fulllength HCVRNA fused with Renilla luciferase (OR6 cells) were cultured on ECMcoated dishes or noncoated plastic dishes (NDs), and treated with human IFNα. In Huh7 cells cultured on coated dishes, the IFNstimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFNstimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFNα treatment, the amount of HCVRNA and viral protein produced by OR6 cells cultured on coated dishes was higher than that produced by cells cultured on NDs. When cells were treated with β1integrinblocking antibody to disrupt the cellmatrix interaction, the ISRE luciferase activity was restored, and the protein expression of ISG was increased, while that of HCV proteins was suppressed. Treatment of cells with integrinlinked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that β1integrinmediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through β1integrinmediated signaling involving ILK and FAK.
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Document Type: Research Article

Affiliations: 1: Department of Internal Medicine, Saga Medical School, Saga University, Saga 8498501, Japan 2: Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 0608638, Japan 3: Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 7008558, Japan

Publication date: January 1, 2018

More about this publication?
  • The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.

    The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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