SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity

Nat Genet. 2001 May;28(1):29-35. doi: 10.1038/ng0501-29.


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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / therapy
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • CpG Islands
  • DNA Methylation*
  • DNA-Binding Proteins / metabolism
  • Gene Silencing*
  • Genes, Tumor Suppressor*
  • Genetic Therapy
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Janus Kinase 2
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / therapy
  • Molecular Sequence Data
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins*
  • Repressor Proteins*
  • STAT3 Transcription Factor
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism
  • Tyrphostins / therapeutic use


  • Antineoplastic Agents
  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Protein-Tyrosine Kinases
  • JAK2 protein, human
  • Janus Kinase 2

Associated data

  • GENBANK/U15422
  • GENBANK/U88326