Background/Aims: The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV) has been implicated in HCV-induced liver pathogenesis. Wnt/β-catenin signaling has also been involved in tumorigenesis. To elucidate the molecular mechanism of HCV pathogenesis, we examined the potential effects of HCV NS5A protein on Wnt/β-catenin signal transduction cascades. Methods: The effects of NS5A protein on β-catenin signaling cascades in hepatic cells were investigated by luciferase reporter gene assay, confocal microscopy, immunoprecipitation assay, and immunoblot analysis. Results: β-Catenin-mediated transcriptional activity is elevated by NS5A protein, in the context of HCV replication, and by infection of cell culture-produced HCV. NS5A protein directly interacts with endogenous β-catenin and colocalizes with β-catenin in the cytoplasm. NS5A protein inactivates glycogen synthase kinase 3β and increases subsequent accumulation of β-catenin in HepG2 cells. β-Catenin was also accumulated in HCV patients' liver tissues. In addition, the accumulation of β-catenin in HCV replicon cells requires both activation of phosphatidylinositol 3-kinase and inactivation of GSK3β. Conclusions: NS5A activates β-catenin signaling cascades through increasing the stability of β-catenin. This modulation is accomplished by the protein interplay between viral and cellular signaling transducer. These data suggest that NS5A protein may directly be involved in Wnt/β-catenin-mediated liver pathogenesis.
Bibliographical noteFunding Information:
We thank Dr. Takaji Wakita (National Institute of Infectious Disease, Tokyo) for providing us with an HCV JFH-1 cDNA clone. This study was supported by a grant from the National R&D program for Cancer Control, Ministry of Health & Welfare (0620100), Korea, National Research Laboratory (ROA-2007-000-20051-0) and Biotechnology Development (2008-04100) from the Ministry of Education, Science and Technology, Korea.
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