The effect of vincristine on miRNA genes methylation in gastric cancer

Gastric cancer is an aggressive disease with high incidence in the world. Epigenetic factors as well as genetic factors are also influential in gastric cancer formation and progress. Epigenetic mechanisms include DNA methylation, histone modifications and RNA interference. CpG islands in the promoter region of tumor suppressor genes display intense hypermethylation in gastric cancer. These changes in the genome might lead to mutations, chromatin instability and transcriptional silencing of tumor suppressor genes. High or low expression of miRNAs effect tumorigenesis, proliferation, invasion and metastasis in gastric cancer. The methylation status of miRNAs affect irregular expression of miRNAs in the cancer pathogenesis. It has been reported that low expression miR335, miR34a and miR9-3, which are tumor suppressor in gastric cancer. This low expression has been reported to be due to hypermethylation in miRNA genes. In this study we aimed to investigate the effect of decitabine, a DNMT inhibitory agent, and vincristine, a chemotherapeutic drug, on the hypermethylation effect of genes; miR335, miR34a and miR9-3, which are tumor suppressor genes with low expression in AGS and MKN45 gastric cancer cell lines. As a result of comparative analysis with control group and decitabine group, it has been found that vincristine increases methylation of miR335 gene in AGS cells and decreases methylation in MKN45 cells. Vincristine has been demonstrated to increase demethylation in the miR34a and miR9-3 genes in both cell lines, depending on the time. As a result of vincristine treatment, the expression level of pri-miR335 decreased in AGS cells and increased in MKN45 cells. In addition, expression levels of pri-miR34a and pri-miR9-3 were determined to enhance in both cell lines. Findings show that there is a relation between the methylation status and expression levels of miRNAs. Therefore, it has been found that vincristine affects gene-specific methylation in gastric cancer.