Deletion of the SOCS3 Gene in Liver Parenchymal Cells Promotes Hepatitis-Induced Hepatocarcinogenesis

Hisanobu Ogata, Takashi Kobayashi, Takatoshi Chinen, Hiromi Takaki, Takahito Sanada, Yasumasa Minoda, Keiko Koga, Giichi Takaesu, Yoshihiko Maehara, Mitsuo Iida, Akihiko Yoshimura

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Abstract

Background & Aims: 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 (SOCS3fl/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-γ 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.

Original languageEnglish
Pages (from-to)179-193
Number of pages15
JournalGastroenterology
Volume131
Issue number1
DOIs
Publication statusPublished - 2006 Jul

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Ogata, H., Kobayashi, T., Chinen, T., Takaki, H., Sanada, T., Minoda, Y., Koga, K., Takaesu, G., Maehara, Y., Iida, M., & Yoshimura, A. (2006). Deletion of the SOCS3 Gene in Liver Parenchymal Cells Promotes Hepatitis-Induced Hepatocarcinogenesis. Gastroenterology, 131(1), 179-193. https://doi.org/10.1053/j.gastro.2006.04.025