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

Abstract

BackgroundThe 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/β-catenin signaling is a major factor in oncogenesis of HCC. However, the pathogenesis of HCV core-associated Wnt/β-catenin activation remains to be further characterized. Therefore, we attempted to determine whether HCV core protein plays an important role in regulating Wnt/β-catenin signaling in HCC cells.MethodologyWnt/β-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 FindingsHCV core protein significantly enhances Tcf-dependent transcriptional activity induced by Wnt3A in HCC cell lines. Additionally, core protein increases and stabilizes β-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3β, 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/SignificanceHCV core protein enhances Wnt/β-catenin signaling activity, hence playing an important role in HCV-associated carcinogenesis.

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

“…accumulation of ␤-catenin in human hepatoma cells (59,60). Furthermore, our findings suggest the critical involvement of HCV-induced OPN on the phosphorylation of Akt via ␣V␤3 and CD44 (Fig.…”

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…Direct activation of the Wnt/β-catenin pathway was demonstrated in an in vitro model also separately for the core (C) protein of HCV [9,10,91]. HCVcore transfected Huh7 cells up-regulated Wnt-1 and WISP-2 transcription [91].…”

“…In both studies by Liu et al, core protein of HCV amplified the TCF-dependent transcriptional activity, intensified expression and stabilized β-catenin at the protein level in Huh7 cells through inactivation of GSK-3β. It proved to be responsible for amplification of cell proliferation and promotion of tumor growth following action of one of the Wnt pathway ligands, the Wnt-3a protein [9,10]. Core protein of HCV increases active β-catenin and nuclear accumulation in SMMC-7721 cells.…”

“…Already at the beginning of this century more numerous mutations of β-catenin were found to develop in HCV-associated HCC than with HBV-related HCC [5]. Recent years have brought the results of studies on direct interactions between oncogenic HCV proteins and components of the Wnt/β-catenin signaling pathway [6][7][8][9][10].…”

LncRNA HANR Promotes Tumorigenesis and Increase of Chemoresistance in Hepatocellular Carcinoma

“…A recent study also reported that the protein level of GSK3β is significantly lower in HCC tissues than in normal liver tissues and that reduced levels correlate with advanced clinicopathological characteristics and poorer prognosis [18]. In addition, both hepatitis B virus X protein and hepatitis C virus core protein activate the oncogenic Wnt pathway through the inactivation of GSK-3β [19,20]. As a direct inhibitor, GSK3β interaction protein (GSKIP) negatively regulates GSK3β and downstream Wnt signaling pathway, which is consistent with an oncogenic role of GSKIP in tumor growth [21].…”