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Cited by 161Liver physiology and pathologyCytokine Signaling Pathways and InteractionsHepatocellular Carcinoma Treatment and Prognosis

Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3

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Riehle, Kimberly J., Campbell, Jean S., McMahan, Ryan S., Johnson, Melissa M., Beyer, Richard P., Bammler, Theo K., Fausto, Nelson·2008·The Journal of Experimental Medicine
DOI 10.1084/jem.20070820PMC PMC2234364
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Abstract

Suppressor of cytokine signaling 3 (SOCS3) down-regulates several signaling pathways in multiple cell types, and previous data suggest that SOCS3 may shut off cytokine activation at the early stages of liver regeneration (Campbell, J.S., L. Prichard, F. Schaper, J. Schmitz, A. Stephenson-Famy, M.E. Rosenfeld, G.M. Argast, P.C. Heinrich, and N. Fausto. 2001.J. Clin. Invest. 107:1285–1292). We developed Socs3 hepatocyte-specific knockout (Socs3 h-KO) mice to directly study the role of SOCS3 during liver regeneration after a two-thirds partial hepatectomy (PH). Socs3 h-KO mice demonstrate marked enhancement of DNA replication and liver weight restoration after PH in comparison with littermate controls. Without SOCS3, signal transducer and activator of transcription 3 (STAT3) phosphorylation is prolonged, and activation of the mitogenic extracellular signal-regulated kinase 1/2 (ERK1/2) is enhanced after PH. In vitro, we show that SOCS3 deficiency enhances hepatocyte proliferation in association with enhanced STAT3 and ERK activation after epidermal growth factor or interleukin 6 stimulation. Microarray analyses show that SOCS3 modulates a distinct set of genes, which fall into diverse physiological categories, after PH. Using a model of chemical-induced carcinogenesis, we found that Socs3 h-KO mice develop hepatocellular carcinoma at an accelerated rate. By acting on cytokines and multiple proliferative pathways, SOCS3 modulates both physiological and neoplastic proliferative processes in the liver and may act as a tumor suppressor.

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Authors
Riehle, K. J., Campbell, J. S., McMahan, R. S., Johnson, M. M., Beyer, R. P., Bammler, T. K., & Fausto, N.
Affiliations
  • 1Department of Pathology
  • University of Washington (US)
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2007-12-24
Volume
205
Issue
1
Pages
91-103
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20070820
PMC
PMC2234364
OpenAlex
W2117962285
Cited by
161
References
60
Citations by year
2026: 2 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 11 · 2016: 5 · 2015: 10 · 2014: 7 · 2013: 14 · 2012: 19
FWCI
7.53
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • University of Washington (P30ES07033)
  • National Institutes of Health (CA23226, P30ES07033)
  • National Cancer Institute (R01CA023226, CA023226, CA 23226, R37CA023226, CA 074131, R01CA074131)
  • National Institute of Environmental Health Sciences (P30 ES-07033, P30ES007033)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
Keywords
SOCS3, liver regeneration, hepatocarcinogenesis, hepatocyte-specific knockout mice, partial hepatectomy, STAT3 phosphorylation, ERK1/2 activation, hepatocyte proliferation, epidermal growth factor, interleukin-6, cytokine signaling, tumor suppressor, hepatocellular carcinoma, gene expression profiling
MeSH terms
Suppressor of Cytokine Signaling 3 Protein, Animals, DNA Replication, Enzyme Inhibitors, Liver, Liver Neoplasms, Liver Regeneration, Mitosis, Organ Size, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Hepatocytes, Cell Proliferation, Suppressor of Cytokine Signaling Proteins, Mice

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