Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression.
OBJECTIVE
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.
Miyoshi
Hideyuki
H
Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Fujie
Hajime
H
Shintani
Yoshizumi
Y
Tsutsumi
Takeya
T
Shinzawa
Seiko
S
Makuuchi
Masatoshi
M
Kokudo
Norihiro
N
Matsuura
Yoshiharu
Y
Suzuki
Tetsuro
T
Miyamura
Tatsuo
T
Moriya
Kyoji
K
Koike
Kazuhiko
K
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D018936:Hepatitis C Antigens / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014758:Viral Core Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D018936:Hepatitis C Antigens; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014758:Viral Core Proteins; C499352:core protein p22, Hepatitis C virus