Enhancement of Canonical Wnt/β-Catenin Signaling Activity by HCV Core Protein Promotes Cell Growth of Hepatocellular Carcinoma Cells

Background: The Hepatitis C virus (HCV) core protein has been implicated as a potential oncogene or a cofactor in HCV-related hepatocellular carcinoma (HCC), but the underlying mechanisms are unknown. Overactivation of the Wnt/beta-catenin signaling is a major factor in oncogenesis of HCC. However, the pathogenesis of HCV core-associated Wnt/beta-catenin activation remains to be further characterized. Therefore, we attempted to determine whether HCV core protein plays an important role in regulating Wnt/b-catenin signaling in HCC cells. Methodology: Wnt/b-catenin signaling activity was investigated in core-expressing hepatoma cells. Protein and gene expression were examined by Western blot, immunofluorescence staining, RT-qPCR, and reporter assay. Principal Findings: HCV core protein significantly enhances Tcf-dependent transcriptional activity induced by Wnt3A in HCC cell lines. Additionally, core protein increases and stabilizes b-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3 beta, which contributes to the up-regulation of downstream target genes, such as c-Myc, cyclin D1, WISP2 and CTGF. Also, core protein increases cell proliferation rate and promotes Wnt3A-induced tumor growth in the xenograft tumor model of human HCC. Conclusions/Significance: HCV core protein enhances Wnt/b-catenin signaling activity, hence playing an important role in HCV-associated carcinogenesis.