Deletion of the SOCS3 Gene in Liver Parenchymal Cells Promotes Hepatitis–Induced Hepatocarcinogenesis

Ogata, Hisanobu; Kobayashi, Takashi; Chinen, Takatoshi; Takaki, Haruyuki; Sanada, Takahito; Minoda, Yasumasa; Koga, Katsumi; Takaesu, Giichi; Maehara, Yoshihiko; Iida, Mitsuo; Yoshimura, Akihiko

doi:10.1053/j.gastro.2006.04.025

Cited by 167 publications

(140 citation statements)

References 49 publications

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“…Furthermore, these anti-proliferative effects of SOCS3 appear to protect against development and growth of colonic tumors during chronic intestinal inflammation, because VC/HO mice show enhanced tumor size, number and burden after AOM/DSS. Our findings in the AOM/DSS model of CAC demonstrate a tumor suppressor role of SOCS3 during chronic colitis and are consistent with a recent report that hepatocyte-specific SOCS3 deletion promotes hepatitis C associated hepatocellular carcinoma (Ogata et al, 2006b). Promoter hypermethylation and silencing of SOCS3 genes has been reported in liver (Niwa et al, 2005), lung (He et al, 2003) and squamous cell carcinoma of the head and neck (Weber et al, 2005).…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have shown that SOCS3 exerts negative feedback effects on IL-6 signaling in macrophages, hepatocytes and Caco2 colon cancer cells (Croker et al, 2003;Wang et al, 2003;Yasukawa et al, 2003;Ogata et al, 2006b). We demonstrate here that SOCS3 overexpression reduces basal proliferation of IEC-6, and Caco2 cells, providing new evidence that SOCS3 can exert anti-proliferative effects in non-transformed IEC and colon cancer cell lines.…”

Section: Discussionsupporting

confidence: 68%

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Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

et al. 2007

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 68%

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

et al. 2007

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“…The frequent inactivation of SOCS3 by DNA methylation in CMPD is consistent with a potential role of SOCS3 as a tumour suppressor gene. In other tissue models, namely lung and liver, it is notable that restoration of SOCS3 expression induces apoptosis and growth suppression, whereas deletion of the SOCS3 gene co-operates to enhance carcinogenesis (He et al, 2003;Ogata et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia‐negative chronic myeloproliferative disorders

Capello¹,

Deambrogi²,

Rossi

et al. 2008

Br J Haematol

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SummaryPh-negative chronic myeloproliferative disorders (CMPD) are characterized by constitutive Janus kinase-signal transducer and activator of transcription (JAK-STAT) activation. SOCS3, SOCS1 and PTPN6 (SHP1) are negative regulators of the JAK-STAT pathway. We investigated epigenetic and genetic inactivation of SOCS3, SOCS1 and PTPN6 in 112 CMPD and 20 acute myeloid leukaemia (AML) post-CMPD. SOCS3 methylation occurred at high frequency in both CMPD (46/112; 41AE1%) and AML post-CMPD (10/17; 58AE8%) and was associated with transcriptional silencing. In contrast, methylation of SOCS1 and PTPN6 was observed in only a fraction of CMPD (15/112, 13AE4% for SOCS1; and 8/112, 7AE1% for PTPN6) and AML post-CMPD (3/20, 15% for SOCS1; and 1/20, 5% for PTPN6). No somatic mutations of SOCS1 were found in CMPD. SOCS3, SOCS1 and PTPN6 methylation occurred in both JAK2V617F-positive (35AE1% for SOCS3; 14AE9% for SOCS1; 8AE1% for PTPN6) and JAK2V617F-negative (57AE1% for SOCS3; 14AE3% for SOCS1; and 9AE5% for PTPN6) CMPD. These data indicate that methylation of SOCS3 and, to a lesser extent, SOCS1 and PTPN6 is a frequent event in both JAK2V617F-positive and -negative CMPD and may act as an alternative or complementary mechanism to JAK2 mutations, enhancing cytokine signal transduction. The frequent inactivation of SOCS3 is a novel finding in CMPD with potential implications for the molecular pathology of these disorders.

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“…79,[121][122][123] Evidence suggests a complex molecular interplay related to these inflammatory cytokines that leads to hepatocyte death, compensatory proliferation, and ultimately carcinogenesis. 122 NF-jB regulates immune and inflammatory responses and is activated in many tumors, inhibiting apoptosis.…”

mentioning

confidence: 99%

Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection

2010

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Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

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Deletion of the SOCS3 Gene in Liver Parenchymal Cells Promotes Hepatitis–Induced Hepatocarcinogenesis

Cited by 167 publications

References 49 publications

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon

Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia‐negative chronic myeloproliferative disorders

Nonalcoholic fatty liver disease and hepatocellular carcinoma: A weighty connection

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