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Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production

Oncogene volume 25, pages 2520–2530 (2006)Cite this article

Abstract

Recently, DNA methylation and reduced expression of the suppressor of the cytokine signaling-3 (SOCS3) gene in human hepatocellular carcinoma (HCC) patients have been reported. However, the roles of SOCS3 in HCC development in vivo have not been clarified. Using RT–PCR analysis and Western blotting, we confirmed that SOCS3 expression was reduced in HCC patients. However, reduced expression of SOCS3 occurred not only in HCC but also in nontumor regions, and this reduction was stronger as the fibrosis grade increased. Furthermore, SOCS3 levels were inversely correlated with signal transducers and activators of transcription-3 (STAT3) activation as well as transforming growth factor (TGF)-β1 levels in the non-HCC region. To define the molecular consequences of SOCS3 silencing/STAT3 hyperactivation and liver fibrosis, we examined liver-specific SOCS3-deficient mice. We demonstrated that SOCS3 deletion in the liver resulted in hyperactivation of STAT3 and promoted ConA- and chemical-induced liver fibrosis. The expression of TGF-β1, a mediator of fibrosis, was enhanced by SOCS3 gene deletion, but suppressed by the overexpression of a dominant-negative STAT3 or SOCS3 both in vivo and in vitro. These data suggest that TGF-β1 is a target gene of STAT3 and could be one of the mechanisms for enhanced fibrosis in SOCS3-deficient mice. Thus, our present study provides a novel role of SOCS3 and STAT3 in HCC development: in addition to the previously characterized oncogenic potentials, STAT3 enhances hepatic fibrosis through the upregulation of TGF-β1 expression, and SOCS3 prevents this process.

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Abbreviations

JAK:

Janus kinase

STAT:

signal transducers and activators of transcription

SOCS:

suppressor of cytokine signaling

TGF:

transforming growth factor

AST:

aspartate aminotransferase

ALT:

alanine aminotransferase

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Acknowledgements

We thank Y Kawabata and T Yoshioka for their help, Mr T Kinoshita, Ms M Othsu, Ms Y Yamada, Mr M Sasaki, and Ms E Fujimoto (Technical Support Center, Medical Institute of Bioregulation) for technical assistance, and Y Nishi for manuscript preparation. This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan, the Haraguchi Memorial Foundation, the Yamanouchi Foundation for Research on Metabolic Disorders, the Takeda Science Foundation, the Mochida Memorial Foundation, the Kato Memorial Foundation, and the Uehara Memorial Foundation.

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  1. T Yoshida

    Present address: Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, 830-0011, Japan

Authors and Affiliations

  1. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Fukuoka, Japan

    H Ogata, T Chinen, T Yoshida, I Kinjyo, G Takaesu, H Shiraishi, T Kobayashi & A Yoshimura

  2. Department of Medicine and Clinical Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    H Ogata & M Iida

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  1. H Ogata
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Correspondence to A Yoshimura.

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Ogata, H., Chinen, T., Yoshida, T. et al. Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production. Oncogene 25, 2520–2530 (2006). https://doi.org/10.1038/sj.onc.1209281

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