A SNP of miR-146a is involved in bladder cancer relapse by affecting the function of bladder cancer stem cells via the miR-146a signallings

MiR-146a-5p in urine samples was recently reported to be possibly used as a prognostic marker for bladder cancer (BC). Interestingly, YAP1 and COX2 were both demonstrated to function as stem cell regulators in BC. Therefore, in this study, we aimed to establish the molecular mechanism underlying the role of miR-146a, YAP1 and COX2 in BC relapse. We also studied the possibility of using the C > G genotype of miR-146a rs2910164 SNP as an indicator of BC relapse. A total of 170 BC patients were assigned into different groups based on their genotypes of rs2910164 SNP. Kaplan-Meier survival curves were plotted to compare the recurrence-free rate among these groups. Real-time PCR, Western Blot, bioinformatic analysis, luciferase assay and IHC assay were conducted to study the role of rs2910164 SNP in the progression of BC. Accordingly, GC/CC-genotyped patients presented a higher risk of recurrence when compared with GG-genotyped patients, while the expression of BC regulators was influenced by the presence of rs2910164. COX2 mRNA and YAP1 mRNA were, respectively, validated as direct target genes of miR-146a, and the expression of YAP1 and COX2 mRNA/protein was both suppressed by miR-146a precursors. The expression of ALDH1A1 mRNA/protein was inhibited upon the down-regulation of YAP1, while the expression of let7 and SOX2 mRNA/protein was inhibited upon the down-regulation of COX2. In conclusion, two signalling pathways, miR-146a/YAP1/ALDH1A1 and miR-146a/COX2/PGE2/let7/SOX2, were modulated by miR-146a. As an SNP regulating the expression of miR-146a, the rs2910164 G > C SNP could be utilized as a biomarker for BC relapse.