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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

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 met...

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Autores principales: Kim, Seung-Kyoon, Jang, Hay-Ran, Kim, Jeong-Hwan, Kim, Mirang, Noh, Seung-Moo, Song, Kyu-Sang, Kang, Gyeong Hoon, Kim, Hee Jin, Kim, Seon-Young, Yoo, Hyang-Sook, Kim, Yong Sung
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516490/
https://www.ncbi.nlm.nih.gov/pubmed/18635522
http://dx.doi.org/10.1093/carcin/bgn110
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author Kim, Seung-Kyoon
Jang, Hay-Ran
Kim, Jeong-Hwan
Kim, Mirang
Noh, Seung-Moo
Song, Kyu-Sang
Kang, Gyeong Hoon
Kim, Hee Jin
Kim, Seon-Young
Yoo, Hyang-Sook
Kim, Yong Sung
author_facet Kim, Seung-Kyoon
Jang, Hay-Ran
Kim, Jeong-Hwan
Kim, Mirang
Noh, Seung-Moo
Song, Kyu-Sang
Kang, Gyeong Hoon
Kim, Hee Jin
Kim, Seon-Young
Yoo, Hyang-Sook
Kim, Yong Sung
author_sort Kim, Seung-Kyoon
collection PubMed
description 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.
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spelling pubmed-25164902009-02-25 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 Kim, Seung-Kyoon Jang, Hay-Ran Kim, Jeong-Hwan Kim, Mirang Noh, Seung-Moo Song, Kyu-Sang Kang, Gyeong Hoon Kim, Hee Jin Kim, Seon-Young Yoo, Hyang-Sook Kim, Yong Sung Carcinogenesis Carcinogenesis 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. Oxford University Press 2008-08 2008-07-16 /pmc/articles/PMC2516490/ /pubmed/18635522 http://dx.doi.org/10.1093/carcin/bgn110 Text en © The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
spellingShingle Carcinogenesis
Kim, Seung-Kyoon
Jang, Hay-Ran
Kim, Jeong-Hwan
Kim, Mirang
Noh, Seung-Moo
Song, Kyu-Sang
Kang, Gyeong Hoon
Kim, Hee Jin
Kim, Seon-Young
Yoo, Hyang-Sook
Kim, Yong Sung
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Carcinogenesis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516490/
https://www.ncbi.nlm.nih.gov/pubmed/18635522
http://dx.doi.org/10.1093/carcin/bgn110
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