Hepatitis C virus NS3 protein enhances cancer cell invasion by activating matrix metalloproteinase-9 and cyclooxygenase-2 through ERK/p38/NF-κB signal cascade

Lili Lu; Qi Zhang; Kailang Wu; Xi Chen; Yi Zheng; Chengliang Zhu; Jianguo Wu

doi:10.1016/j.canlet.2014.09.027

Hepatitis C virus NS3 protein enhances cancer cell invasion by activating matrix metalloproteinase-9 and cyclooxygenase-2 through ERK/p38/NF-κB signal cascade

Cancer Lett. 2015 Jan 28;356(2 Pt B):470-8. doi: 10.1016/j.canlet.2014.09.027. Epub 2014 Oct 8.

Authors

Lili Lu¹, Qi Zhang², Kailang Wu², Xi Chen², Yi Zheng², Chengliang Zhu³, Jianguo Wu⁴

Affiliations

¹ State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China; Wuhan University of Science and Technology, Wuhan 430081, China.
² State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China.
³ State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China; Renmin Hospital, Wuhan University, Wuhan 430060, China.
⁴ State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: jwu@whu.edu.cn.

PMID: 25305454
DOI: 10.1016/j.canlet.2014.09.027

Abstract

Hepatitis C virus (HCV) infection causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, the mechanisms by which HCV causes the diseases are largely unknown. Here, we elucidated the effects of HCV on the invasion and migration of hepatoma cells, with the aim to reveal the mechanism by which HCV infection induces HCC. We initially showed that matrix metalloproteinase-9 (MMP-9) was elevated in the sera of HCV-infected patients, and demonstrated that HCV nonstructural protein 3 (NS3) activated MMP-9 transcription through nuclear factor-κB (NF-κB) by stimulating translocation of NF-κB from cytosol to the nucleus to enhance its binding to MMP-9 promoter. In addition, cyclooxygenase-2 (COX-2) and extracellular signal-regulated kinase (ERK1/2)/mitogen-activated protein kinase (p38) pathway were involved in HCV-activated MMP-9 expression. Moreover, NS3 enhanced hepatoma cell invasion and migration through MMP-9 and COX-2. Thus, this study provides new insights into the roles of HCV NS3, MMP-9 and COX-2 in regulating cancer cell invasion.

Keywords: Cancer cell invasion; Cyclooxygenase-2; Hepatitis C virus; Hepatocellular carcinoma; Matrix metalloproteinase-9.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Blotting, Western
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Carcinoma, Hepatocellular / virology
Case-Control Studies
Cell Movement
Cell Proliferation
Cyclooxygenase 2 / genetics
Cyclooxygenase 2 / metabolism*
Electrophoretic Mobility Shift Assay
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
Flow Cytometry
Hepacivirus / physiology
Hepatitis C / metabolism
Hepatitis C / pathology
Hepatitis C / virology
Humans
Immunoenzyme Techniques
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Liver Neoplasms / virology
Matrix Metalloproteinase 9 / genetics*
Matrix Metalloproteinase 9 / metabolism
NF-kappa B / genetics
NF-kappa B / metabolism*
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Cells, Cultured
Viral Nonstructural Proteins / genetics
Viral Nonstructural Proteins / metabolism*
Wound Healing
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

NF-kappa B
NS3 protein, hepatitis C virus
RNA, Messenger
Viral Nonstructural Proteins
Cyclooxygenase 2
PTGS2 protein, human
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
MMP9 protein, human
Matrix Metalloproteinase 9