Abstract
Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe liver fibrosis that are established with long-lasting inflammation of the liver. Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative regulator of cytokine signaling, by DNA methylation has been implicated in development or progress of HCC. However, how SOCS1 contributes to HCC is unknown. We examined SOCS1 gene methylation in >200 patients with chronic liver disease and found that the severity of liver fibrosis is strongly correlated with SOCS1 gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice with haploinsufficiency of the SOCS1 gene (SOCS1(-/+) mice) developed more severe liver fibrosis than did wild-type littermates (SOCS1(+/+) mice). Moreover, carcinogen-induced HCC development was also enhanced by heterozygous deletion of the SOCS1 gene. These findings suggest that SOCS1 contributes to protection against hepatic injury and fibrosis, and may also protect against hepatocarcinogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biopsy
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / immunology*
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / prevention & control
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Choline Deficiency / genetics
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Choline Deficiency / immunology
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Choline Deficiency / pathology
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DNA Methylation
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DNA, Neoplasm / genetics
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Disease Models, Animal
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Gene Silencing
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Humans
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Intracellular Signaling Peptides and Proteins*
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Liver Cirrhosis / genetics*
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Liver Cirrhosis / immunology
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Liver Cirrhosis / pathology
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Liver Neoplasms / genetics
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Liver Neoplasms / immunology*
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Liver Neoplasms / pathology
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Liver Neoplasms / prevention & control
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Mice
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Mice, Knockout
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Polymerase Chain Reaction / methods
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Repressor Proteins / genetics
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Repressor Proteins / physiology*
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
Substances
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Carrier Proteins
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DNA, Neoplasm
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Intracellular Signaling Peptides and Proteins
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Repressor Proteins
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SOCS1 protein, human
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Socs1 protein, mouse
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins