SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis

Yoshida, Takafumi; Ogata, Hisanobu; Kamio, Masaki; Joo, Akiko; Shiraishi, Hiroshi; Tokunaga, Yoshiharu; Sata, Michio; Nagai, Hisaki; Yoshimura, Akihiko

doi:10.1084/jem.20031675

Cited by 167 publications

(146 citation statements)

References 29 publications

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“…Aberrant SOCS-3 methylation in tumor tends to accompany progressed fibrosis in the nontumorous part. Consistent with the report by Yoshida et al (2004), SOCS-1-methylation also correlated with severity of fibrosis in our samples (data not shown). Advanced fibrosis might accelerate the development of HCC in association with activated JAK/STAT pathway.…”

Section: Discussionsupporting

confidence: 81%

“…Concomitant methylation was also observed in family genes such that p15 and p16 were methylated in leukemia (Herman et al, 1997), and ASCL and ASC were methylated in HCC (Kubo et al, 2004). SOCS-1 methylation was reported to correlate with severity of liver fibrosis (Yoshida et al, 2004 (Table 1a). The distributions of tumor types were similar between SOCS-3-methylated and unmethylated HCC samples.…”

Section: Discussionmentioning

confidence: 99%

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Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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We identified that suppressor of cytokine signaling-3 (SOCS-3) gene was aberrantly methylated in its CpG island in three of 10 human hepatocellular carcinoma (HCC) cell lines. SOCS-3 RNA was undetectable in five of the 10 HCC cell lines including the three methylated cell lines, and a demethylating agent, 5-aza-2 0 -deoxycytidine, reactivated SOCS-3 expression in three cell lines tested. The DNA region where we found aberrant DNA methylation includes a signal transducers and activators of transcription (STAT) binding consensus sequence. When the DNA region was used as a promoter, DNA methylation markedly reduced promoter activity. SOCS-3 was also aberrantly methylated in six of 18 primary HCC samples. SOCS-3 expression was reduced in three of the three methylated and one of the three unmethylated primary samples examined. Restoration of SOCS-3 in cells lacking SOCS-3 expression suppressed STAT3 phosphorylation and cell growth. We found that IL-6 acted as a growth factor in HCC cells. Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth. In addition, AG490, a chemical JAK2 inhibitor, suppressed cell growth and downregulated STAT3 phosphorylation, but not FAK phosphorylation. We also found that SOCS-3 physically interacted with phosphorylated FAK and Elongin B in HCC cells. Restoration of SOCS-3 decreased FAK phosphorylation as well as FAK protein level. Inhibition of SOCS-3 expression increased FAK phosphorylation, resulting in enhancement of cell migration. These data indicate that SOCS-3 negatively regulates cell growth and cell motility by inhibiting Janus kinase (JAK)/STAT and FAK signalings in HCC cells. Thus, loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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“…MMP-9 attacks and degrades basement membrane collagens and gelatins of all types [28,29]. Polymorphonuclear leukocytes (PMNs) and endothelial cells contain large amounts of MMP-9 in secretory vesicles [30], which enable the rapid release of MMP-9 following specific stimuli [31]. MMP-9 has been shown to cleave inactive TNF-␣ and release activated TNF-␣ [32].…”

Section: Discussionmentioning

confidence: 99%

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Chen

et al. 2006

J Biochem & Molecular Tox

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Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno-ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine-choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2) S-adenosylmethionine (SAMe), or (3) 2(RS)-n-propylthiazolidine-4(R)-carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups ( p < 0.01). Serum transaminases were considerably elevated (AST: 5.8-fold; ALT: 3.22-fold) in MCD rats. However, administration of GSH-enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT-PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen-␣1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and TGF-␤) in the livers of rats fed MCD. GSH-enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. C

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“…Primers and probes for GAPDH (TaqMan GAPDH control reagent kit, Foster City, CA, USA) were purchased from Perkin-Elmer Applied Biosystems. Real-time quantitative PCR was done using the ABI Prism 7000 Sequence Detection System (Perkin-Elmer Applied Biosystems, Foster City, CA, USA), as described previously (Yoshida et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

et al. 2006

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Aberrant activation of the Ras/Raf-1/extracellular-regulated kinase (ERK) pathway has been shown to be involved in the progression of human hepatocellular carcinoma (HCC). However, the mechanism of dysregulation of ERK activation is poorly understood. Recently, we identified Sprouty-related protein with Ena/vasodilator-stimulated phosphoprotein homology-1 domain (Spred) as a physiological inhibitor of the Ras/Raf-1/ ERK pathway. In this study, we found that the expression levels of Spred-1 and -2 in human HCC tissue were frequently decreased, comparing with those in adjacent non-tumorous tissue. Moreover, Spred expression levels in HCC tissue were inversely correlated with the incidence of tumor invasion and metastasis. Forced expression of Spred-1 inhibited HCC cell proliferation in vitro and in vivo, which was associated with reduced ERK activation. Spred-1 overexpression also reduced the secretion of matrix metalloproteinase-9 (MMP-9) and MMP-2, which play important roles in tumor invasion and metastasis. In addition, Spred-1 inhibited growth factor-mediated HCC cell motility. These data indicate that the reduction of Spred expression in HCC is one of the causes of the acquisition of malignant features. Thus, Spred could be not only a novel prognostic factor but also a new therapeutic target for human HCC.

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SOCS1 Is a Suppressor of Liver Fibrosis and Hepatitis-induced Carcinogenesis

Cited by 167 publications

References 29 publications

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors

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