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Carcinogenesis Advance Access originally published online on July 16, 2008
Carcinogenesis 2008 29(8):1623-1631; 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
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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, Seon-Young Kim1, Hyang-Sook Yoo1 and Yong Sung Kim1,2,*

1 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology
2 Department of Functional Genomics, University of Science and Technology, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-806, Republic of Korea
3 Department of General Surgery
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

* To whom correspondence should be addressed. Tel: +82 42 879 8110; Fax: +82 42 879 8119; Email: 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 reverse transcription–polymerase chain reaction analysis of 77 paired primary gastric tumor samples revealed that 38% of analyzed tumors had a >2-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 knock down of TCF4 using small interfering RNA 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.

Abbreviations: 5-aza-dC, 5-aza-2'-deoxycytidine; bHLH, basic helix-loop-helix; ChIP, chromatin immunoprecipitation; GFP, green fluorescence protein; LOE, loss of expression; mRNA, messenger RNA; MSP, methylation-specific polymerase chain reaction; PCR, polymerase chain reaction; RLGS, restriction landmark genomic scanning; RT, reverse transcription; siRNA, small interfering RNA; TCF4, transcription factor 4; TSA, trichostatin A

{dagger} These authors contributed equally to this work.

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


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