Abstract 2221: DNA methylation of microRNA genes in gastric carcinoma and its clinicopathological association
Authors: Jin-Sook Kim, Ga-Eon Kim, Ji-Hee Lee, Jun-Eul Hwang, Woo-Kyun Bae, Jae-Hyuk Lee
Journal: Cancer Research (2011)

Abstract Background: Epigenetic silencing of tumor-related genes, due to CpG island methylation, is considered to be an important mechanism for the development of many tumors, including gastric carcinoma (GC). DNA methylation of multiple CpG sites in promoter region of several tumor-related genes, such as hMLH1, p14, p16, and APC has been analyzed in GC so far. MicroRNAs (miRNA) are small, non-coding RNAs that can contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies indicate that epigenetic silencing of miRNAs with tumor suppressor activity by CpG island methylation plays an important role in gastric carcinogenesis. To explore the role of epigenetic mechanisms in the down-regulation of miRNA genes (has-miR-9, has-miR-129, has-miR-137), we examined the presence of DNA methylation-associated silencing of miRNAs in GC and observed that aberrant methylation of these miRNAs is associated with expression of target gene products. Materials and Methods: The extent of promoter methylation of 4 miRNA genes (has-miR-9-1, has-miR-9-3, has-miR-129-2, has-miR-137) was assessed using methylation-specific polymerase chain reaction (MSP) in 100 GC tissues (50 early gastric cancers and 50 advanced gastric cancers) and corresponding non-tumor tissues. Twenty patients with benign gastric pathology were also included as a control group. The potential target gene products of miRNAs were studied by immunohistochemistry and the relationship between methylation profile of miRNAs promoter and clinicopathological parameters was analyzed. Results: Methylation of the has-miR-9-3 and has-miR-137 CpG island was frequently observed in tumor tissues (89% and 86%, respectively) and non-tumor tissues in 100 GC patients (70% and 78%), but not in normal gastric tissues (55% and 55%). Methylation of the has-miR-9-1 is slightly higher in tumor tissues (65%) than normal gastric tissue (45%). However, methylation level of the has-miR-129-2 was not shown significant difference in tumor tissues (97%) compared with non-tumor tissues (90%) and normal gastric tissues (90%). Expression of NF-κB and SOX4 protein, which are has-miR-9 and has-miR-129-2 potential target respectively, were inversely correlated with methylation level of miRNAs. The presence of H. pylori infection was significantly associated with aberrant methylation of miRNA genes (p&amp;lt;0.05). But, there was no significant correlation between aberrant methylation of miRNAs and other clinicopathological factors. Conclusion: These results suggest that specific miRNAs methylation in GC could be an important molecular mechanism causing loss of control on its target, and it may be correlated with the high transcriptional activity of target gene. Epigenetic silencing of some miRNAs may involve in the early stage of gastric carcinogenesis and could be used as an efficient diagnostic biomarker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2221. doi:10.1158/1538-7445.AM2011-2221