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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

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dc.contributor.authorKim, Seung-Kyoon-
dc.contributor.authorJang, Hay-Ran-
dc.contributor.authorKim, Jeong-Hwan-
dc.contributor.authorKim, Mirang-
dc.contributor.authorNoh, Seung-Moo-
dc.contributor.authorSong, Kyu-Sang-
dc.contributor.authorKang, Gyeong Hoon-
dc.contributor.authorKim, Hee Jin-
dc.contributor.authorKim, Seon-Young-
dc.contributor.authorYoo, Hyang-Sook-
dc.contributor.authorKim, Yong Sung-
dc.date.accessioned2009-06-04T06:45:56Z-
dc.date.available2009-06-04T06:45:56Z-
dc.date.issued2008-07-16-
dc.identifier.citationCarcinogenesis, 29, 1623-1631en
dc.identifier.issn0143-3334 (print)-
dc.identifier.issn1460-2180 (online)-
dc.identifier.urihttps://hdl.handle.net/10371/4420-
dc.description.abstractTranscriptional 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.en
dc.description.sponsorship21C Frontier Functional Human Genome Project (FG08-11-01) from the Ministry of Science and Technology of Korea.en
dc.language.isoen-
dc.publisherOxford University Pressen
dc.titleCpG 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 cancersen
dc.typeArticleen
dc.contributor.AlternativeAuthor김승균-
dc.contributor.AlternativeAuthor장해란-
dc.contributor.AlternativeAuthor김정환-
dc.contributor.AlternativeAuthor김미랑-
dc.contributor.AlternativeAuthor노승무-
dc.contributor.AlternativeAuthor송규상-
dc.contributor.AlternativeAuthor강경훈-
dc.contributor.AlternativeAuthor김희진-
dc.contributor.AlternativeAuthor김선영-
dc.contributor.AlternativeAuthor유향숙-
dc.contributor.AlternativeAuthor김용성-
dc.identifier.doi10.1093/carcin/bgn110-
dc.identifier.doi10.1093/carcin/bgn110-
dc.citation.journaltitleCarcinogenesis-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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