Abstract

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.

Highlights

  • This inhibition of proliferation was confirmed by induction of cell arrest in G2/M phase (Figure 5H). These results demonstrated that the β-catenin pathway was activated through the inactivation of glycogen synthase kinase-3β (GSK-3β) in chronic hepatitis C virus (HCV) infection to promote both cell proliferation and colony-forming ability but knockdown of β-catenin decreased cell proliferation and induced apoptosis, and that Wnt/β-catenin signaling activation remained after HCV eradication by either IFN or direct-acting antivirus agents (DAA), but metformin reversed it through protein kinase A (PKA)/GSK3β-mediated β-catenin degradation and inhibited cell proliferation and colony-forming ability as well as increased apoptosis (Figure 6)

  • We indicated for the first time that Wnt/β-catenin signaling remained activated, HCV were eradiated by DAA (Figure 5A,D), which can be used to explain why patients who received DAA had a high incidence of hepatocellular carcinoma (HCC) while HCC was considerably reduced compared with active HCV infection

  • Given that Wnt/β-catenin signaling remained activated in chronic HCV infection despite virus clearance by DAA, there would be two possibilities for this phenomenon

Read more

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Chronic hepatitis C virus (HCV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC). Deaths caused by chronic HCVinduced HCC increased by 21.1% [1]. HCV is a positive-sense single-stranded RNA virus with 9.6 kb in length and is unable to integrate into the host genome [2,3]. The HCV genomes encodes a single polyprotein. The polyprotein is processed by cellular and viral proteases to generate 10 polypeptides including three structural proteins

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call