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rdf:type |
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lifeskim:mentions |
umls-concept:C0025723,
umls-concept:C0086418,
umls-concept:C0205160,
umls-concept:C0205548,
umls-concept:C0441655,
umls-concept:C0805732,
umls-concept:C1150611,
umls-concept:C1335960,
umls-concept:C1366753,
umls-concept:C1426208,
umls-concept:C1548425,
umls-concept:C1704259,
umls-concept:C1704735,
umls-concept:C1705987,
umls-concept:C2239176
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pubmed:issue |
1
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pubmed:dateCreated |
2001-4-30
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pubmed:databankReference |
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/JAK2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/SOCS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/STAT3 Transcription Factor,
http://linkedlifedata.com/resource/pubmed/chemical/STAT3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Suppressor of Cytokine Signaling...,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-cyano-(3,4-dihydroxy)-N-benzyl...
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1061-4036
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
28
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
29-35
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11326271-Antineoplastic Agents,
pubmed-meshheading:11326271-Carcinoma, Hepatocellular,
pubmed-meshheading:11326271-Carrier Proteins,
pubmed-meshheading:11326271-CpG Islands,
pubmed-meshheading:11326271-DNA Methylation,
pubmed-meshheading:11326271-DNA-Binding Proteins,
pubmed-meshheading:11326271-Gene Silencing,
pubmed-meshheading:11326271-Gene Therapy,
pubmed-meshheading:11326271-Genes, Tumor Suppressor,
pubmed-meshheading:11326271-Humans,
pubmed-meshheading:11326271-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:11326271-Janus Kinase 2,
pubmed-meshheading:11326271-Liver Neoplasms,
pubmed-meshheading:11326271-Molecular Sequence Data,
pubmed-meshheading:11326271-Protein-Tyrosine Kinases,
pubmed-meshheading:11326271-Proto-Oncogene Proteins,
pubmed-meshheading:11326271-Repressor Proteins,
pubmed-meshheading:11326271-STAT3 Transcription Factor,
pubmed-meshheading:11326271-Signal Transduction,
pubmed-meshheading:11326271-Suppressor of Cytokine Signaling Proteins,
pubmed-meshheading:11326271-Trans-Activators,
pubmed-meshheading:11326271-Tyrphostins
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pubmed:year |
2001
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pubmed:articleTitle |
SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.
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pubmed:affiliation |
The Johns Hopkins University School of Medicine, The Oncology Center, Baltimore, Maryland, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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