Epigenetic silencing of miR-137 is a frequent event in gastric carcinogenesis

Abstract

MicroRNAs (miRNA) are involved in posttranscriptional regulation of gene expression and are dysregulated during carcinogenesis. CpG island methylation of miR-137 is a common event in different cancers; however, the role of miR-137 in gastric cancer (GC) remains largely unexplored. In this study we aimed to characterize the epigenetic alterations of miR-137 in gastric carcinogenesis. We analyzed total 295 tissues including paired primary gastric cancer (T-GC) with corresponding adjacent gastric mucosa (N-GC), paired primary colorectal cancer (CRC) tissues with corresponding non-tumorous mucosa, gastric tissues from controls (N), and patients with chronic/atrophic gastritis (CG) with and without Helicobacter pylori infection. Bisulfite pyrosequencing and TaqMan RT-PCR were used to analyze miR-137 methylation and expression, respectively. Survival differences were evaluated using Kaplan-Meier analyses. miR-137 CpG island methylation was more frequent in tumorous compared to non-tumorous conditions and higher in CRC than in GC. In comparison to N-GC, miR 137 methylation level was lower in N and CG tissues, which correlates with Correas cascade. MiR-137 methylation inversely correlates with global LINE-1 methylation and miR-137 expression. miR-137 methylation was higher in intestinal type GC compared to diffuse one, and higher in antrum compared to cardia and corpus, however, miR-137 methylation was associated with worse prognosis in diffuse, but not in intestinal type of GC. The expression in colon was significantly higher compared to any gastric tissues suggesting functional difference. In summary, miR-137 methylation is a frequent event in gastrointestinal cancers which occurs early in stepwise manner during gastric carcinogenesis and inversely correlates with global methylation. © 2015 Wiley Periodicals, Inc.

Aberrant methylation-mediated silencing of microRNAs contributes to HPV-induced anchorage independence

“…However, also in these studies, differences between normal and cancer were small (on average ~3x increase). Comparable to our results, also in these studies high background methylation was observed in normal samples [45, 53, 56]. Described targets of hsa-miR-137 so far include CDK6, LSD1, RTVP1, CAR and CDC42 [45, 46, 49, 54, 57, 58].…”

LINE-1 hypomethylation is not a common event in preneoplastic stages of gastric carcinogenesis

“…For instance, we have previously reported site-specific CpG island promoter hypermethylation of miR-137 in GC tissue samples, which was inversely correlated with LINE-1 methylation status 25 . In the present study, in the line with the previous reports, we confirmed decreased methylation of LINE-1 in T-CRC compared to N-CRC 26, 27 .…”

“…Global DNA hypomethylation and CpG island promoter hypermethylation are characteristic features of various tumors 13, 25 . For instance, we have previously reported site-specific CpG island promoter hypermethylation of miR-137 in GC tissue samples, which was inversely correlated with LINE-1 methylation status 25 .…”

“…Study design and tissue collection protocol has been partly described in the previous study 25, 35 . For the LINE-1 methylation analyses, we had available 267 tissue specimens (biopsies and surgical material) including: 80 GC tumor tissues (T-GC) with corresponding adjacent non-tumorous gastric mucosa (N-GC) from GC patients; normal gastric mucosa tissue from 19 controls (N); 37 gastric antrum tissues from patients with chronic non-atrophic and atrophic gastritis with/-out intestinal metaplasia (CG); 24 primary CRC tumor tissues (T-CRC) with corresponding adjacent non-tumorous colonic mucosa (N-CRC).…”

“…DNA for methylation analyses from tissue samples was extracted as described previously 25 . Briefly, DNA was isolated with QIAzol Lysis reagent and chloroform, using the interphase, according to user-developed protocol (QIAGEN, Valencia, CA, USA).…”