Identification of Epigenetic Interactions between miRNA and Gene Expression as Potential Prognostic Markers in Bladder Cancer

Purpose: To identify the role of a set of microRNAs and their target genes and protein expression levels in the pathogenesis of bladder cancer with a muscular invasion (T2-T4) and non-muscular invasion (T1). Methods: In 157 patients, bladder specimen was examined for the expression of a set of miRNAs including let-7a-5p, miRNA-449a-5p, miRNA-145-3P, miRNA-124-3P, miRNA-138-5p, and miRNA-23a-5p and their targeted genes; beta-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1 alpha, and PTEN using the qRT-PCR technique. The prognostic effect of miRNAs and their targeted genes on cancer-specific survival (CSS) was evaluated in pT2-pT4 stages. Results: pT1 was found in 40 patients while pT2-4 was found in 117 patients. The expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P significantly decreased in pT2-4 compared with pT1 (p < 0.001), in contrast, miR-23a-5P increased significantly in pT2-pT4 compared with pT1 (p < 0.001). Moreover, the expression of miR-145 did not show a significant change (p = 0.31). Higher expression levels of WNT7A, beta-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2-pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1 alpha, and PTEN genes were downregulated in pT2-pT4 compared with pT1. Lower CSS was significantly associated with lower expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P. Higher expression of beta-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1 alpha, and PTEN were associated with lower CSS. Conclusion: Our results support let-7a-5P, miR-124-3P, miR-138-5P, and their target genes can be developed as accurate biomarkers for prognosis in bladder cancer with a muscular invasion.