Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis.
OBJECTIVE
A recent study has suggested that the methylation silencing of the suppressor of cytokine signaling-3 (SOCS3), a negative regulator of interleukin-6-related cytokines, could be involved in hepatocellular carcinoma (HCC). However, the roles of SOCS3 in hepatocellular carcinogenesis and hepatitis have not been established. We investigated the effect of deleting the SOCS3 gene on the development of hepatitis and HCC in hepatitis C virus-infected patients and mouse models.


METHODS
The expression of SOCS genes in HCC and non-HCC regions of patient samples was determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The conditional knockout approach in mice was used to determine the hepatocyte-specific roles of SOCS3. To generate a liver-specific deletion, floxed SOCS3 (SOCS3(fl/fl)) mice were crossed with albumin-Cre transgenic mice. Hepatitis and HCC were induced by administering concanavalin A and diethylnitrosamine, respectively.


RESULTS
SOCS3 expression was reduced in the HCC regions compared with the non-HCC regions. Carcinogen-induced hepatic tumor development was enhanced by deletion of the SOCS3 gene, which was associated with higher levels of the targets of signal transducers and activators of transcription (ie, B-cell lymphoma-XL, B-cell lymphoma-2, C-myelocytomatosis, cyclin D1, and vascular endothelial growth factor). In the concanavalin A-mediated hepatitis model, deletion of the SOCS3 gene in the hepatocytes protected against liver injury through suppression of interferon-gamma signaling and induction of the antiapoptotic protein Bcl-XL.


CONCLUSIONS
Deletion of the SOCS3 gene in hepatocytes promotes the activation of STAT3, resistance to apoptosis, and an acceleration of proliferation, resulting in enhanced hepatitis-induced hepatocarcinogenesis.
Ogata
Hisanobu
H
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Graduate School of Medical Science, Kyushu University, Higashiku, Fukuoka, Japan.
Kobayashi
Takashi
T
Chinen
Takatoshi
T
Takaki
Hiromi
H
Sanada
Takahito
T
Minoda
Yasumasa
Y
Koga
Keiko
K
Takaesu
Giichi
G
Maehara
Yoshihiko
Y
Iida
Mitsuo
M
Yoshimura
Akihiko
A
D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications* / Q000235:genetics / Q000473:pathology; D003208:Concanavalin A / Q000633:toxicity; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D012334:RNA, Neoplasm / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics*
D012334:RNA, Neoplasm; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D003208:Concanavalin A