Regulation of interferon signaling and HCV-RNA replication by extracellular matrix

Takuya Kuwashiro, Shinji Iwane, Xia Jinghe, Sachiko Matsuhashi, Yuichiro Eguchi, Keizo Anzai, Kazuma Fujimoto, Toshihiko Mizuta, Naoya Sakamoto, Masanori Ikeda, Nobuyuki Kato, Iwata Ozaki

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


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 HuH-7 human hepatoma cell line and HuH-7 cells were stably transfected with full-length HCV-RNA fused with Renilla luciferase (OR6 cells) were cultured on ECM-coated dishes or non-coated plastic dishes (NDs), and treated with human IFN-α. In Huh-7 cells cultured on coated dishes, the IFN-stimulated response element (ISRE) luciferase activity was measured following ISRE plasmid transfection and the expression of IFN-stimulated genes (ISG) were significantly lower than those in cells cultured on NDs. In addition, after IFN-α treatment, the amount of HCV-RNA 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 β1-integrin-blocking antibody to disrupt the cell-matrix 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 integrin-linked kinase (ILK) inhibitor or focal adhesion kinase (FAK) inhibitor restored the ISRE luciferase activity and expression of ISG proteins. These results suggested that β1-integrin-mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through β1-integrin-mediated signaling involving ILK and FAK.

Original languageEnglish
Pages (from-to)957-965
Number of pages9
JournalInternational journal of molecular medicine
Issue number2
Publication statusPublished - 2018


  • Extracellular matrix
  • Hepatitis C virus
  • Interferon
  • Interferon-stimulated genes
  • β1-integrin

ASJC Scopus subject areas

  • Genetics


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