Hepatitis C Virus Core Protein Exerts an Inhibitory Effect on Suppressor of Cytokine Signaling (SOCS)-1 Gene Expression

J Hepatol. 2005 Nov;43(5):757-63. doi: 10.1016/j.jhep.2005.03.028. Epub 2005 May 31.

Abstract

Background/aims: Suppressor of cytokine signaling (SOCS)-1, a negative feedback regulator of cytokine signaling pathway, also has a tumor suppressor activity, the silencing of its gene by hypermethylation is suggested to contribute to hepatocarcinogenesis. We studied the effect of the core protein of hepatitis C virus (HCV) on the expression of SOCS-1 gene.

Methods: HCV core gene transgenic mice, which develop hepatocellular carcinoma late in life, HepG2 cells expressing the core protein, and human liver tissues were analyzed.

Results: The expression of SOCS-1 gene was significantly suppressed in the liver of core gene transgenic mice and HepG2 cells expressing the core protein, while that of SOCS-3 gene was conserved. SOCS-1 expression levels also decreased in HCV-positive human liver tissues. The core protein differentially down-regulated the expression of signal transducer and activator of transcription (STAT) target genes, but rather enhanced STAT1 and STAT3 activation after interleukin-6 stimulation in mouse liver tissues and cells.

Conclusions: HCV core protein down-regulates the expression of SOCS-1 gene. This is a mechanism leading to SOCS-1 silencing, an alternative to the hypermethylation of the gene; this effect of the core protein may modulate the intracellular signaling pathway, contributing to the pathogenesis in HCV infection including hepatocarcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • CpG Islands
  • DNA Methylation
  • Gene Expression Regulation*
  • Hepacivirus / genetics
  • Hepacivirus / metabolism*
  • Hepatitis C Antigens / metabolism*
  • Humans
  • Liver / cytology
  • Liver / physiology
  • Mice
  • Mice, Transgenic
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Subcellular Fractions / metabolism
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Viral Core Proteins / metabolism*

Substances

  • Carrier Proteins
  • Hepatitis C Antigens
  • Repressor Proteins
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Socs1 protein, mouse
  • Stat1 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Viral Core Proteins
  • core protein p22, Hepatitis C virus