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

Jiao Liu,Ke Chen,Tong-Chuan He,Bingqiang Zhang,Xuefei Cai,Yang Bi,Xiong Ding,Hong Ren,Jia Tang,Xiaoliang Shan,Peng Hu,Fan Zhou,Qingmei Chen,Ni Tang,Ailong Huang,Youde Cao,Ning Ling,Ben C B Ko

doi:10.1371/journal.pone.0027496

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.

Highlights

Hepatocellular carcinoma (HCC) ranks among the most common and deadly cancers worldwide [1]
Hepatitis C virus (HCV) core protein plays an important role in activating Tcf-dependent transcriptional activity in hepatoma cells
There was a dramatic increase in the expression level of c-Myc and cyclin D1 after co-expression of Wnt3A and core in hepatoma cells. These in vivo results suggest that HCV core protein may potentiate Wnt/b-catenin-induced tumor growth in hepatocellular carcinoma (HCC) xenograft model. Both virus-induced and immunologically-mediated hepatocytes damage play an important role in pathogenesis, the mechanisms underlying HCV persistence and pathogenesis have been poorly understood

Summary

Introduction

Hepatocellular carcinoma (HCC) ranks among the most common and deadly cancers worldwide [1]. The mechanisms underlying HCV-associated hepatocarcinogenesis are not fully understood. HCV core is a 191 amino acid protein with RNA binding activity and may transactivate some transcription factors, such as NF-kB, AP-1 and SREBP [5,6,7]. Molecular mechanism underlying HCV-induced neoplastic transformation remains to be thoroughly elucidated. The Hepatitis C virus (HCV) core protein has been implicated as a potential oncogene or a cofactor in HCVrelated hepatocellular carcinoma (HCC), but the underlying mechanisms are unknown. Overactivation of the Wnt/b-catenin signaling is a major factor in oncogenesis of HCC. The pathogenesis of HCV core-associated Wnt/b-catenin activation remains to be further characterized. We attempted to determine whether HCV core protein plays an important role in regulating Wnt/b-catenin signaling in HCC cells

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Results

Conclusion