The NS5A protein of hepatitis C virus transcriptionally upregulates the AGR3 gene expression

Kobe J Med Sci. 2015 Apr 7;61(1):E27-35.

Abstract

The non-structural protein 5A (NS5A) of hepatitis C virus (HCV) is a multifunctional protein involved in the HCV lifecycle and pathogenesis. The precise molecular mechanisms of NS5A-mediated pathogenesis still remain to be clarified. In this study, we performed cDNA microarray analysis on NS5A-expressing HEK293 cells and the non-expressing control to screen the possible cellular genes dysregulated by NS5A. Subsequent quantitative real time PCR (qRT-PCR) analysis on NS5A-expressing cells and the control confirmed that NS5A upregulated the anterior gradient homolog 3 (AGR3) mRNA expression. The domain III of NS5A was responsible for the activation of AGR3 gene expression. AGR3 mRNA expression levels were upregulated also in Huh7.5 cells harboring a full-genome HCV-1b RNA replicon (FGR) and in those infected with HCV-2a. Moreover, AGR3 promoter activity was activated in NS5A-expressing cells, FGR-harboring cells and HCV-infected cells. Taken together, our present results suggest that HCV NS5A transcriptionally activates the cancer-associated AGR3 gene. This may be a novel mechanism of HCV-mediated pathogenesis, especially hepatocarcinogenesis.

Keywords: AGR3; NS5A; gene expression; hepatitis C virus; hepatocellular carcinoma; transcriptional activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular / virology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Gene Expression Profiling
  • Gene Expression Regulation
  • HEK293 Cells
  • Hepatitis C / complications*
  • Hepatitis C / virology
  • Humans
  • Liver Neoplasms / virology*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • Real-Time Polymerase Chain Reaction
  • Viral Nonstructural Proteins / physiology*

Substances

  • AGR3 protein, human
  • Carrier Proteins
  • Neoplasm Proteins
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus