Methylation of Multiple Genes in Gastric Glands with Intestinal Metaplasia

Abstract

Gene silencing by methylation of promoter CpG islands is deeply involved in cancers, but its involvement in polyclonal disorders is still unclear. Here, we analyzed the presence of gene silencing in intestinal metaplasia (IM) of the stomach, a polyclonal disorder, in which multiple gastric glands aberrantly differentiate into those with intestinal characteristics. By a genome-wide screening, CpG islands in the putative promoter regions of four genes (ZIK1, ZNF141, KAL1, and FGF14) were found to be specifically methylated in glands with IM, and their expression was markedly decreased. When demethylation was induced in cell lines with their methylation by 5-aza-2-deoxycytidine, expression of ZIK1, KAL1, and FGF14 was restored, supporting causal roles of methylation in their silencing. Analysis of ZIK1 methylation in a single gland showed that the vast majority of DNA molecules isolated from a gland with IM were methylated and that those from a gland without IM were not. ZIK1 methylation was present in glands isolated from physically distant positions within a stomach, showing that methylation occurred multifocally. These data indicate that methylation of multiple genes occurs independently in multiple glands, each of which has its own stem cell, demonstrating that involvement of aberrant gene silencing in noninherited polyclonal human disorders needs more attention. (Am J Pathol

Influence of IL1B polymorphism on CpG island hypermethylation in Helicobacter pylori-infected gastric cancer

“…After identification of tumors in the endoscopic mucosal biopsy samples through light microscopy, tumor lesions were manually dissected and the dissected tissues were pooled together in a microtube containing lysis buffer and proteinase K. Whole tissue sections were used for DNA extraction of the chronic gastritis group samples. Chronic gastritis cases showing intestinal metaplasia were excluded from the present study because intestinal metaplasia itself is associated with increased DNA hypermethylation of CpG island loci [25] and our preliminary study confirmed this finding. Sodium bisulfite conversion of genomic DNA was performed as described [26].…”

Helicobacter pylori-infection-associated CpG island hypermethylation in the stomach and its possible association with Polycomb repressive marks

“…Because previous studies [18,26] revealed that intestinal metaplasia is accompanied by enhanced promoter CGI hypermethylation compared with chronic gastritis without intestinal metaplasia and our preliminary study revealed enhanced CGI hypermethylation in intestinal metaplasia regardless of H. pylori infection, cases that showed intestinal metaplasia or epithelial neoplasia in any of the four tissue samples were excluded from the study in order to focus on the effect of H. pylori infection on DNA methylation changes in chronic gastritis. Gastric carcinoma cases or chronic gastritis cases without intestinal metaplasia were included in the study.…”

Identification of Novel Proteins Interacting with Vascular Endothelial Growth Inhibitor 174 in Renal Cell Carcinoma

“…In addition to the nine contiguous zinc fingers in the C-terminus, ZIK1 contains a KRAB-A domain thought to be involved in transcriptional repression. ZIK1 demonstrated aberrant DNA methylation, it might function on tumor development (39). It was unknown whether there was a relationship between decreasing VEGI174 expression level and increasing MYC or ZIK1 expression levels in RCC tissues.…”