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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

Oncogene volume 18, pages 7280–7286 (1999)Cite this article

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.

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Abbreviations

TGF-β:

transforming growth factor-β

RII:

type II receptor

RI:

type I receptor

PCR:

polymerase chain reaction

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Acknowledgements

We thank Dr Anita Roberts for helpful discussion and critical review of the manuscript and Mariko Kato for expert technical assistance. This work was supported in part by grants from Korea Science and Engineering Foundation (KOSEF) through the CRC, the HAN Project, and the Korean Ministry of Science and Technology (MOST 8-1-10).

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Authors and Affiliations

  1. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, 20892-5055, Maryland, MD, USA

    Shin Hyeok Kang, Young-Hyuck Im, Han-Kwang Yang, David A Lee, Hwa Young Lee & Seong-Jin Kim

  2. Cancer Research Center, Seoul National University College of Medicine, Seoul, Korea

    Shin Hyeok Kang, Yung-Jue Bang, Ho Soon Lee & Noe Kyeong Kim

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Kang, S., Bang, YJ., Im, YH. et al. 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. Oncogene 18, 7280–7286 (1999). https://doi.org/10.1038/sj.onc.1203146

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