Hepatitis C virus NS4B protein induces epithelial-mesenchymal transition by upregulation of SnailReport as inadecuate




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Virology Journal

, 14:83

Hepatitis viruses

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.

KeywordsHCV Epithelial to mesenchymal EMT Cadherin Snail Hippo pathway AbbreviationsAKTProtein kinase B

DlgDiscs Large

DMEMDulbecco’s modified Eagle medium

EMTEpithelial to mesenchymal transition

EREndoplasmic reticulum

FBSFetal bovine serum

FSPFibroblast-specific protein

HCCHepatocellular carcinoma

HCVHepatitis C virus

LAPLeucine-rich repeats and PDZ domains

LATS1-2Large tumor suppressor kinase 1-2

Lg1Lethal giant larvae

MST1-2Mammalian Ste2-like kinases

NF-κBNuclear factor kappa-light-chain-enhancer of activated B cells

NS4BNon-structural protein 4B

PDZPSD-95-Dlg-A-ZO-1

PI3KPhosphoinositide 3-Kinase

PIK3CBPhosphoinositide 3-Kinase Catalytic Beta Polypeptide

PVDFPolyvinylidene fluoride

SDS-PAGESodium dodecyl sulfate-polyacrylamide gelelectrophoresis

SMASmooth muscle actin

STATSignal transducer and activator of transcription

TAZTranscriptional coactivator with PDZ binding motif

TEADTranscriptional enhancer factor domain family member

TGF-βTransforming growth factor-β

YAPYes-associated protein

ZEBZinc finger E-box-binding protein

ZO-1Zonula occludens-1





Author: Bicheng Hu - Shenggao Xie - Yuqian Hu - Wen Chen - Xiaofan Chen - Yi Zheng - Xinxing Wu

Source: https://link.springer.com/







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