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DNA methylation of genes linked with retinoid signaling in gastric carcinoma
Author(s) -
Shutoh Mariko,
Oue Naohide,
Aung Phyu Phyu,
Noguchi Tsuyoshi,
Kuraoka Kazuya,
Nakayama Hirofumi,
Kawahara Katsunobu,
Yasui Wataru
Publication year - 2005
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21392
Subject(s) - dna methylation , methylation , microbiology and biotechnology , retinoic acid , retinoic acid receptor , biology , gene , cancer research , cpg site , demethylating agent , gene silencing , gene expression , genetics
Abstract BACKGROUND Hypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor β ( RAR β), cellular retinol‐binding protein 1 ( CRBP1 ), and tazarotene‐induced gene 1 ( TIG1 ) genes have been associated with retinoic acid signaling. To the authors' knowledge, little is known regarding the involvement of these three genes in gastric carcinoma (GC). In this study, the authors investigated the methylation status of these genes and analyzed the role of their DNA methylation in GC. METHODS DNA methylation of 3 retinoic acid‐associated genes was analyzed in 42 samples of GC from 42 patients and in 8 GC cell lines by methylation‐specific polymerase chain reaction (PCR) analysis. The mRNA expression levels for these three genes were measured by quantitative reverse transcription‐PCR. RESULTS In 7 of 8 GC cell lines, the CRBP1 gene was hypermethylated, and CRBP1 transcription was inactive. In 6 of 8 GC cell lines, the TIG1 gene was hypermethylated, and TIG1 transcription was inactive. Treatment with demethylating agent 5‐aza‐2′‐deoxycytidine restored both CRBP1 and TIG1 transcription. DNA methylation of the RAR β, CRBP1 , and TIG1 genes was detected in 15 of 42 GC samples (36%), 14 of 42 GC samples (33%), and 4 of 42 GC samples (10%), respectively, and in 6 of 30 samples (20%), 0 of 30 samples (0%), and 1 of 30 samples (3%) of corresponding nonneoplastic mucosa. None of the 10 normal gastric mucosa samples from young, healthy individuals demonstrated hypermethylation of any of these genes. DNA methylation of each gene was associated significantly with low mRNA expression of the respective gene. Twenty‐four of 42 GC samples (57%) demonstrated hypermethylation of at least 1 of the 3 genes. However, no significant, concordant hypermethylation of these genes was observed. CONCLUSIONS The results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling. Cancer 2005. © 2005 American Cancer Society.