Loss of SOCS3 in the liver promotes fibrosis by enhancing STAT3-mediated TGF-β1 production
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)-beta1 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-beta1, 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-beta1 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 potenti…
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Fibrotic tissue samples from patients often show elevated levels of pY-STAT3.
“Fibrotic tissue samples from patients often show elevated levels of pY-STAT3”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Ogata et al., 2006
Cites
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LPS and TNFα induce SOCS3 mRNA and inhibit IL‐6‐induced activation of STAT3 in macrophages
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“Fibrotic tissue samples from patients often show elevated levels of pY-STAT3 (Ogata et al., 2006).”
BackgroundKupffer cells mediate leptin-induced liver fibrosis
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“Consistent with this notion, SOCS3 deficiency in liver cells increased the degree of liver fibrosis (Ogata et al., 2006).”
- Authors
- Ogata, H., Chinen, T., Yoshida, T., Kinjyo, I., Takaesu, G., Shiraishi, H., Iida, M., Kobayashi, T., & Yoshimura, A.
- Affiliations
- Kurume University (JP)
- Kyushu University (JP)
- Corresponding author
- Yoshimura, A
- Venue
- Oncogene
- Published
- 2006-02-13
- Volume
- 25
- Issue
- 17
- Pages
- 2520-2530
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1995049975
- Cited by
- 246
- References
- 7
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 11 · 2023: 12 · 2022: 15 · 2021: 24 · 2020: 17 · 2019: 13 · 2018: 13 · 2017: 11 · 2016: 11 · 2015: 14 · 2014: 15 · 2013: 9 · 2012: 15
- FWCI
- 8.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- SOCS3, STAT3, TGF-β1, liver fibrosis, hepatocellular carcinoma, suppressor of cytokine signaling, DNA methylation, dominant-negative STAT3
- MeSH terms
- Suppressor of Cytokine Signaling 3 Protein, Animals, Gene Expression Regulation, Genes, Dominant, Carcinoma, Hepatocellular, Humans, Liver, Liver Cirrhosis, Liver Neoplasms, Blotting, Western, Transforming Growth Factor beta, Mice, Knockout, Integrases, Reverse Transcriptase Polymerase Chain Reaction, Gene Silencing, STAT3 Transcription Factor, Suppressor of Cytokine Signaling Proteins, Mice, Transforming Growth Factor beta1
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