Epigenetic regulation of MIR145 core promoter controls miR-143/145 cluster in bladder cancer progression and treatment outcome

Owing to its highly heterogeneous molecular landscape, bladder cancer (BlCa) is still characterized by non-personalized treatment and lifelong surveillance. Motivated by our previous findings on miR-143/145 value in disease prognosis, we have studied the underlying epigenetic regulation of the miR-143/ 145 cluster in BlCa. Expression and DNA methylation of miR-143/145 cluster were analyzed in our screening (n = 162) and The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA; n = 412) cohorts. Survival analysis was per-formed using tumor relapse and progression as clinical end-points for non-muscle-invasive bladder cancer (NMIBC; TaT1), while disease progression and patients' death were used for muscle-invasive bladder cancer (MIBC; T2-T4). TCGA-BLCA served as validation cohort. Bootstrap analysis was carried out for internal validation, while decision curve analysis was used to evaluate clinical benefit. TCGA-BLCA and screening cohorts highlighted MIR145 core promoter as the pivotal, epigenetic regulatory region on cluster's expres-sion. Lower methylation of MIR145 core promoter was associ-ated with aggressive disease phenotype, higher risk for NMIBC short-term progression, and poor MIBC survival. MIR145 methylation-fitted multivariate models with established disease markers clearly enhanced patients' risk stratification and prediction of treatment outcome. MIR145 core promoter methylation was identified as a potent epigenetic regulator of miR-143/145 cluster, supporting modern personalized risk stratification and management in BlCa.