DNA methylation of genes linked with retinoid signaling in gastric carcinoma

Abstract

BACKGROUNDHypermethylation of CpG islands has been associated with silencing of various tumor suppressor genes, and the retinoid acid receptor β (RARβ), 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.METHODSDNA 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.RESULTSIn 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 RARβ, 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.CONCLUSIONSThe results suggested that gastric carcinogenesis involves transcriptional inactivation by aberrant DNA methylation of genes related to retinoid signaling. Cancer 2005. © 2005 American Cancer Society.

G protein-coupled receptor kinase 5 mediates Tazarotene-induced gene 1-induced growth suppression of human colon cancer cells

“…Loss of TIG1 expression through promoter DNA hypermethylation occurs in many tumour tissues [5-11], suggesting that the loss of TIG1 provides a survival advantage to tumour cells. This notion is supported by findings from this and previous studies [2,7,10] demonstrating the growth and invasion suppressive activities of TIG1 in prostate, endometrial, nasopharyngeal, and colon cancer cells.…”

“…The TIG1 gene, located on chromosome 3q25.32, is expressed in most normal tissues [2]. Loss of chromosome 3q heterozygocity has been reported in cancer tissues [3-5], while downregulation of TIG1 expression through promoter hypermethylation has been reported to occur in various carcinomas, including nasopharyngeal, esophageal, prostate, and colon [5-11]. …”

Use of integrative epigenetic and cytogenetic analyses to identify novel tumor-suppressor genes in malignant melanoma

“…Its expression has been associated with spontaneous regression of melanoma in an animal model[52]. RARRES1 is a putative tumor suppressor in prostate cancer [53]and demonstrates promoter hypermethylation in gastric carcinoma [54]. Down-regulation of expression in different cancer cell lines is related to hypermethylation of the promoter [55] It is posited that silencing of RARRES1 by promoter hypermethylation is common in human cancers and may contribute to the loss of retinoic acid responsiveness in some neoplastic cells[55].…”

Tazarotene-Induced Gene 1 Enhanced Cervical CellAutophagy through Transmembrane Protein 192

“…Although latexin is considered a carboxypeptidase inhibitor, TIG1’s proteolytic activity remains unknown. TIG1 suppressed the growth and invasion of several types of cancer cells, and CpG hypermethylation of the TIG1 promoter led to downregulation of TIG1 expression in various carcinomas (Chen et al, 2014; Jing et al, 2002; Kwok et al, 2009; Kwong et al, 2005; Mizuiri et al, 2005; Peng et al, 2012; Shutoh et al, 2005; Wu et al, 2006; Yanatatsaneejit et al, 2008; Zhang et al, 2004). Expression of TIG1 is decreased in malignant prostate carcinoma cell lines and in poorly differentiated colorectal adenocarcinoma, but TIG1 is present in benign or well-differentiated tumor lines (Jing et al, 2002; Wu et al, 2006), and ectopic TIG1 expression led to suppression of growth in cancer cells (Jing et al, 2002; Tsai et al, 2011; Wu et al, 2011).…”