title: Hepatitis C virus infection induces the expression of amphiregulin, a factor related to the activation of cellular survival pathways and required for efficient viral assembly.
abstract: Amphiregulin (AREG) is a ligand of the epidermal growth factor (EGF) receptor and may play a role in the development of cirrhosis and hepatocellular carcinoma in patients infected with hepatitis C virus (HCV). AREG showed an enhanced expression in HCV-infected human hepatoma cells according to gene array analysis. Therefore, we addressed the question about the role of AREG in HCV infection. AREG expression level was elevated in hepatoma cells containing a subgenomic HCV replicon or infected by HCV. Using a reporter assay, AREG promoter activity was found to be upregulated upon HCV infection. The enhanced AREG expression in hepatoma cells was partly caused by dsRNAs, HCV NS3 protein and autocrine stimulation. AREG was able to activate cellular signalling pathways including ERK, Akt and p38, promote cell proliferation, and protect cells from HCV-induced cell death. Further, knockdown of AREG expression increased the efficiency of HCV entry, as proven by HCV pseudoparticles reporter assay. However, the formation and release of infectious HCV particles were reduced by AREG silencing with a concomitant accumulation of intracellular HCV RNA pool, indicating that the assembly and release of HCV progeny may require AREG expression. Blocking the MAPK-ERK pathway by U0126 in Huh7.5.1 cells had a similar effect on HCV replication. In conclusion, HCV infection leads to an increase in AREG expression in hepatocytes. AREG expression is essential for efficient HCV assembly and virion release. Due to the activation of the cellular survival pathways, AREG may counteract HCV-induced apoptosis of infected hepatocytes and facilitate the development of liver cirrhosis and hepatocellular carcinoma.
authors.affiliation: Graduate University of Chinese Academy of Sciences, Beijing, PR China.|Institute of Virology, University Hospital of Essen, Essen, Germany.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Rongjuan
authors.initials: R
authors.lastname: Pei
authors.affiliation: Graduate University of Chinese Academy of Sciences, Beijing, PR China.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Honghe
authors.initials: H
authors.lastname: Chen
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Graduate University of Chinese Academy of Sciences, Beijing, PR China.|Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Beckebaum
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany.
authors.forename: Vito
authors.initials: V
authors.lastname: Cicinnati
authors.affiliation: Institute of Virology, University Hospital of Essen, Essen, Germany.
authors.forename: Mengji
authors.initials: M
authors.lastname: Lu
authors.affiliation: Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, PR China.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D066258:Amphiregulin; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D066255:EGF Family of Proteins; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000096:biosynthesis*; D016174:Hepacivirus / Q000472:pathogenicity*; D006526:Hepatitis C / Q000473:pathology* / Q000821:virology*; D022781:Hepatocytes / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D019065:Virus Assembly; D057074:Virus Release; D055815:Young Adult
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins