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Carcinogenesis Advance Access published online on July 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn110
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

CpG methylation in exon 1 of Transcription Factor 4 increases with age in normal gastric mucosa and is associated with gene silencing in intestinal type gastric cancers

Seung-Kyoon Kim1,2,{dagger}, Hay-Ran Jang1,{dagger}, Jeong-Hwan Kim1,{dagger}, Mirang Kim1,2, Seung-Moo Noh3, Kyu-Sang Song4, Gyeong Hoon Kang5, Hee Jin Kim1, Seun-Young Kim1, Hyang-Sook Yoo1 and Yong Sung Kim1,2,*

1 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB)
2 Department of Functional Genomics, University of Science and Technology (UST), 52 Eoeun-dong, Yuseong-gu, Daejeon 305-806, Republic of Korea
3 Department of General Surgery, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea
4 Department of Pathology, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea
5 Department of Pathology, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea

* Corresponding author: Phone: 82-42-879-8110; Fax: 82-42-879-8119; E-mail: yongsung{at}kribb.re.kr

Transcriptional factor 4 (TCF4), encoding a basic helix-loop-helix transcriptional factor, has recently been demonstrated as a causative gene for Pitt-Hopkins syndrome, a neurodevelopmental disease. Examination of gastric cancers using the restriction landmark genomic scanning technique revealed methylation at a NotI enzyme site in TCF4 intron 8 and further identified CpG dinucleotide hypermethylation in TCF4 exon 1, strongly associated with gene silencing in gastric cancer cell lines. Treatment with 5-aza-2'-deoxycytidine and/or trichostatin A restored TCF4 expression in TCF4-silenced gastric cancer cell lines. Real-time RT-PCR analysis of 77 paired primary gastric tumor samples revealed that 38% of analyzed tumors had a greater than two-fold decrease in TCF4 expression compared with adjacent normal-appearing tissue, and the decrease significantly correlated with increased CpG methylation in TCF4 exon 1. Clinicopathologic data showed that decreased TCF4 expression occurred significantly more frequently in intestinal type (22/37, 59%) than in diffuse type (7/37, 19%) gastric cancers (P = 0.0004) and likewise more frequently in early (12/18, 67%) than in advanced (17/59, 29%) gastric cancers (P = 0.004). CpG methylation markedly increased with patient age among normal-appearing tissues, suggesting that CpG methylation in gastric mucosa may be one of the earliest events in carcinogenesis of intestinal type gastric cancers. Furthermore, ectopic expression of TCF4 decreased cell growth in a gastric cancer cell line, and the knockdown of TCF4 using siRNA increased cell migration. Based on these results, we propose that the observed frequent epigenetic-mediated TCF4 silencing plays a role in tumor formation and progression.

Key Words: gastric cancer • TCF4 • RLGS • CpG methylation • aging • proliferation • migration

{dagger} These authors contributed equally to this work.

Received December 21, 2007; revised April 25, 2008; accepted April 30, 2008.


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