Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line

Br J Cancer. 2004 Oct 4;91(7):1335-41. doi: 10.1038/sj.bjc.6602133.


The interleukin-mediated Janus kinase (JAK)/STAT pathway plays a crucial role in carcinogenesis. Recently, increased STAT3 activity was found in hepatocellular carcinoma and multiple myeloma in which there was silencing of SOCS-1 (suppressor of cytokine signalling-1) by gene promoter hypermethylation. We investigated the expression level of interleukin-6 (IL-6) and SOCS-1 in gastric cancer cell lines. Expression of SOCS-1 correlated with IL-6 level in most of the cell lines, except for AGS cells in which SOCS-1 was absent despite a high level of IL-6 production. Methylation analysis by methylation-specific polymerase chain reaction and bisulphite sequencing revealed that CpG island of SOCS-1 was densely methylated in AGS cells. Demethylation treatment by 5'aza-deoxycytidine restored SOCS-1 expression and also suppressed constitutive STAT3 phosphorylation in AGS cells. Moreover, methylation of SOCS-1 was detected in 27.5% (11 of 40) of primary gastric tumours samples, 10% (one of 10) of adjacent noncancer tissues but not in any (zero of nine) normal gastric mucosa. Methylation of SOCS-1 also correlated with the loss of mRNA expression in some primary gastric cancers. In conclusion, this is the first report to demonstrate that hypermethylation of SOCS-1 led to gene silencing in gastric cancer cell line and primary tumour samples. Downregulation of SOCS-1 cooperates with IL-6 in the activation of JAK/STAT pathway in gastric cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / biosynthesis
  • Carrier Proteins / metabolism*
  • Cell Transformation, Neoplastic
  • DNA Methylation
  • DNA-Binding Proteins / pharmacology*
  • Down-Regulation
  • Humans
  • Interleukin-6 / pharmacology*
  • Intracellular Signaling Peptides and Proteins*
  • Janus Kinase 1
  • Protein-Tyrosine Kinases / pharmacology*
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Repressor Proteins / biosynthesis
  • Repressor Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor
  • Stomach Neoplasms / pathology*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / pharmacology*
  • Tumor Cells, Cultured


  • Carrier Proteins
  • DNA-Binding Proteins
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Protein-Tyrosine Kinases
  • JAK1 protein, human
  • Janus Kinase 1