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

Abstract

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; β-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1α, 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, β-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2–pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1α, 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 β-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1α, 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.