Hepatitis C virus NS4B protein induces epithelial-mesenchymal transition by upregulation of Snail

Bicheng Hu,Xinxing Wu,Yuqian Hu,Shenggao Xie,Yi Zheng,Xiaofan Chen,Wen Chen

doi:10.1186/s12985-017-0737-1

Abstract

BackgroundChronic hepatitis C virus (HCV) infection is an important cause of hepatocellular carcinoma (HCC). Epithelial to mesenchymal transition (EMT) is a key process associated with tumor metastasis and poor prognosis. HCV infection, HCV core and NS5A protein could induce EMT process, but the role of NS4B on EMT remains poorly understood.MethodsWe overexpressed HCV NS4B protein in HepG2 cells or Huh7.5.1 cells infected by HCVcc, the E-cadherin expression, N-cadherin expression and the EMT-associated transcriptional factor Snail were determined. The migration and invasion capabilities of the transfected cells were evaluated using wound-healing assay. Additionally, we used Snail siRNA interference to confirm the relation of HCV NS4B and Snail on EMT promotion.ResultsHCV NS4B increased the expression of EMT related markers and promoted cell migration and invasion. Snail knock-down almost completely eliminated the function of NS4B protein in EMT changes and reversed cell migration capacity to lower level. HCV NS4B protein could reduce the expression of Scribble and Hippo signal pathway were subsequently inactivated, resulting in the activation of PI3K/AKT pathway, which may be the reason for the up-regulation of Snail.ConclusionsThis study demonstrates that HCV NS4B protein induces EMT progression via the upregulation of Snail in HCC, which may be a novel underlying mechanism for HCV-associated HCC development, invasion and metastasis.

Highlights

Chronic hepatitis C virus (HCV) infection is an important cause of hepatocellular carcinoma (HCC)
HCVcc-infected cells presented the changes of Epithelial to mesenchymal transition (EMT) and upregulation of Snail Huh7.5.1 cells were infected with HCVcc for 48 h and the cells not infected as control group
These results revealed that EMT process really occurred in HCVcc infection cells and the initiation of EMT may be due to upregulation of Snail

Summary

Introduction

Chronic hepatitis C virus (HCV) infection is an important cause of hepatocellular carcinoma (HCC). The epithelial-mesenchymal transition (EMT) is a fundamental biological process by which epithelial cells lose their cell polarity and cell-cell adhesion, undergo a transition from an epithelial phenotype to a mesenchymal phenotype and gain migratory and invasive properties. It can take place in a variety of biological processes, including embryonic development, morphogenesis, tissue repair, carcinogenesis and metastasis [1, 2]. HCV core protein can repress the expression of E-cadherin and up-regulate the mesenchymal phenotypic markers, such as fibronectin, vimentin and N-cadherin, driving EMT procession [13]. Recent evidence indicates HCV core protein can directly inhibit the expression of E-cadherin via hypermethylation of the promoter region of E-cadherin gene by elevating levels of DNA methyltransferase 1 and 3b [14]

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Discussion

Conclusion