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

Open Access
Publisher Website
Google Scholar
Abstract
The transforming growth factor-β (TGF-β) signaling pathway subserves an essential tumor suppressor function in various cell types. A heteromeric complex composed of TGF-β type I (RI) and type II (RII) receptors is required for TGF-β signaling. We have identified a subset of human gastric cancer cell lines which are insensitive to TGF-β and which express a low level of TGF-β type I receptor mRNA relative to a gastric cancer cell line which is highly responsive to TGF-β. Using these cells, we show that hypermethylation of a CpG island in the 5′ region of the TGF-β RI gene provides another potentially important mechanism of escape from negative growth control by TGF-β. 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-β RI gene, but not the RII gene. Transient transfection of an RI expression vector into the TGF-β resistant SNU-601 cell line restores TGF-β responsiveness. These findings suggest that one of the mechanisms of escape from autocrine or paracrine growth control by TGF-β during carcinogenesis could involve aberrant methylation of CpG islands in the 5′ region of the TGF-β RI gene.