Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / therapeutic use
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Carcinoma, Hepatocellular / genetics*
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Carcinoma, Hepatocellular / therapy
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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CpG Islands
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DNA Methylation*
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DNA-Binding Proteins / metabolism
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Gene Silencing*
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Genes, Tumor Suppressor*
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Genetic Therapy
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Humans
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Intracellular Signaling Peptides and Proteins*
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Janus Kinase 2
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Liver Neoplasms / genetics*
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Liver Neoplasms / therapy
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Molecular Sequence Data
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins*
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Repressor Proteins*
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STAT3 Transcription Factor
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Signal Transduction
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Tyrphostins / therapeutic use
Substances
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Antineoplastic Agents
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Carrier Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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SOCS1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Tyrphostins
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alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2
Associated data
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GENBANK/U15422
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GENBANK/U88326