Transcriptional repression of the transforming growth factor-beta type I receptor gene by DNA methylation results in the development of TGF-beta resistance in human gastric cancer

Oncogene. 1999 Dec 2;18(51):7280-6. doi: 10.1038/sj.onc.1203146.


The transforming growth factor-beta (TGF-beta) signaling pathway subserves an essential tumor suppressor function in various cell types. A heteromeric complex composed of TGF-beta type I (RI) and type II (RII) receptors is required for TGF-beta signaling. We have identified a subset of human gastric cancer cell lines which are insensitive to TGF-beta and which express a low level of TGF-beta type I receptor mRNA relative to a gastric cancer cell line which is highly responsive to TGF-beta. Using these cells, we show that hypermethylation of a CpG island in the 5' region of the TGF-beta RI gene provides another potentially important mechanism of escape from negative growth control by TGF-beta. This hypermethylation was found in four of five human gastric cancer cell lines and five out of 40 (12.5%) primary tumors examined. In human gastric cancer cell lines, treatment with the demethylating agent, 5-aza-2'-deoxycytidine, resulted in increased expression of the TGF-beta RI gene, but not the RII gene. Transient transfection of an RI expression vector into the TGF-beta resistant SNU-601 cell line restores TGF-beta responsiveness. These findings suggest that one of the mechanisms of escape from autocrine or paracrine growth control by TGF-beta during carcinogenesis could involve aberrant methylation of CpG islands in the 5' region of the TGF-beta RI gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Methylation*
  • DNA, Neoplasm / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Receptors, Transforming Growth Factor beta / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Tumor Cells, Cultured


  • DNA, Neoplasm
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta