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

Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 02/2008; 205(1):91-103. DOI: 10.1084/jem.20070820
Source: PubMed


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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    • "We screened the 500 base pairs (bp) upstream of each gene from cluster A for over-representation of transcription factor binding sites using PAINT v 3.9 (Vadigepalli et al. 2003; Riehle et al. 2008) and the TRANSFAC Professional v 2009.2 database (Wingender et al. 1996) (Table 3 "

    Full-text · Dataset · Jan 2014
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    • "The pivotal role of JAK/STAT-3 pathway in inflammation-related liver cancer was confirmed by SOCS knocking out studies [152–154]. In fact, Socs3−/− mice were more susceptible to DEN-induced HCC and developed tumors increased in number and size [153, 154]. Furthermore, the inhibition of STAT-3 and NF-κB signaling pathways blocks the TAM-induced upregulation of B7-H1 on HCC cells [71]. "
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.
    Full-text · Article · Mar 2013
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    • "These findings suggest that cytokine activation is not an absolute requirement for liver regeneration, and, together with previous studies, they also suggest that cytokine activation after PH may have both positive and negative effects on hepatocyte proliferation [23–25]. In this regard, the deletion of suppressor-of-cytokine-signaling- (SOCS-) 3 in hepatocytes, a gene that is highly induced in an IL-6 dependent manner, has been shown to confer enhanced proliferative capacity to hepatocytes after PH [25]. The marked attenuation of IL-6 signaling and Socs3 induction reported in Myd88 KO mice demonstrated in prior studies [13, 15] could thus be a potential explanation for the preservation of liver regeneration in Myd88-IFNAR double-KO mice. "
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    ABSTRACT: Liver regeneration is known to occur in mice lacking one or more Toll-like receptors (TLRs) or the adaptor protein MyD88. Though MyD88 is required for signaling by many TLRs, others signal via MyD88-independent pathways, leading to the induction of type I interferons (IFNs). Here, we assessed liver regeneration after partial hepatectomy (PH) in mice lacking both MyD88 and the type I IFN receptor ( Myd88-IFNAR double-KO). Approximately 28% of Myd88-IFNAR double-KO mice had gross liver lesions prior to surgery. In mice without lesions, Myd88-IFNAR deficiency abrogated the increase in circulating IL-6 after PH but did not impair hepatocyte BrdU incorporation, mitotic figure counts, or recovery of liver-to-body weight ratios. These results indicate that type I IFNs are not responsible for the preservation of liver regeneration in Myd88 -deficient mice, and they also cast doubt on the idea of microbial products being essential triggers of liver regeneration in mice undergoing PH.
    Full-text · Article · Dec 2011 · Gastroenterology Research and Practice
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