Regulation of interferon signaling and HCV­RNA replication by extracellular matrix.

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 ß1­integrin­blocking 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 ß1­integrin­mediated signals affected the IFN signaling and promoted HCV replication. Therefore, the accumulation of ECM in liver fibrosis may impair IFN signaling through ß1­integrin­mediated signaling involving ILK and FAK.

Vitamin K and hepatocellular carcinoma: The basic and clinic.

Vitamin K (VK), which was originally identified as a cofactor involved in the production of functional coagulation factors in the liver, has been shown to be involved in various aspects of physiological and pathological events, including bone metabolism, cardiovascular diseases and tumor biology. The mechanisms and roles of VK are gradually becoming clear. Several novel enzymes involved in the VK cycle were identified and have been shown to be linked to tumorigenesis. The VKs have been shown to suppress liver cancer cell growth through multiple signaling pathways via the transcription factors and protein kinases. A VK2 analog was applied to the chemoprevention of hepatocellular carcinoma (HCC) recurrence after curative therapy and was shown to have beneficial effects, both in the suppression of HCC recurrence and in patient survival. Although a large scale randomized control study failed to demonstrate the suppression of HCC recurrence, a meta-analysis suggested a beneficial effect on the long-term survival of HCC patients. However, the beneficial effects of VK administration alone were not sufficient to prevent or treat HCC in clinical settings. Thus its combination with other anti-cancer reagents and the development of more potent novel VK derivatives are the focus of ongoing research which seeks to achieve satisfactory therapeutic effects against HCC.