유전자 특이적 DNA 메틸화의 가이드로서 microRNA의 가능성 탐구

Abstract

Objective: DNA methylation is known as an important factor in epigenetic regulation of gene expression and has been reported to be closely associated with the development of many types of cancer. Aberrant regulation of gene expression due to changes in DNA methylation patterns of specific genes has frequently been reported in tumor cells. However, a clear explanation of the specific mechanisms by which DNA methylation is induced in certain genes has not yet been established. Therefore, in this study, we targeted microRNAs that can specifically recognize DNA sequences and match various genes to investigate the correlation between microRNA and promoter methylation. We aim to explore statistically significant target microRNAs and genes as potential guides for promoter methylation of specific genes. Method: A total of 734 microRNAs and the methylation levels of 54,531 gene promoter clusters were analyzed using Spearman's rank correlation in publicly available databases. After selecting target pairs (miRNA-gene cluster) with higher relative microRNA expression and lower false discovery rate (FDR), the dependent relationships of these identified targets were further validated through linear regression analysis. Result: Through simple linear regression analysis, 25 target genes whose promoter methylation is induced by the expression levels of four target microRNAs (hsa-miR-200a, hsa-miR-200b, hsa-miR-200c and hsa-miR-141) were identified (Positive correlation: β > 0, p < 0.05; Negative correlation: β < 0, p < 0.05), and statistically significant correlations were found between the promoter methylation levels of these genes and their mRNA expression levels regardless of the positive or negative correlation. In the comparison of the cancer group divided into eight categories according to miRNA expression patterns, the correlation between the level of the four miRNAs expression and methylation of each target gene was best explained in cancer group 1, which includes colorectal, gastric, lung, and ovarian cancer. Genes such as ST14, a tumor suppressor gene, and OVOL1 and EPCAM, which are associated with tumor invasion and metastasis, were identified as target genes in this study. Conclusion: Using bioinformatics-based screening analysis, we discovered target gene pairs that exhibit statistically significant changes in promoter methylation patterns due to specific miRNA expression, utilizing large-scale open data. We were able to confirm the possibility that the expression of genes related to tumor formation, invasion, and metastasis can be regulated by promoter methylation induced by microRNAs. This expands our understanding of the mechanism underlying tumor development through methylation and provides a new perspective on the utilization of microRNAs in the field of cancer treatment.