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

Katerina-Marina Pilala; Maria-Alexandra Papadimitriou; Konstantina Panoutsopoulou; Petros Barbarigos; Panagiotis Levis; Georgios Kotronopoulos; Konstantinos Stravodimos; Andreas Scorilas; Margaritis Avgeris

doi:10.1016/j.omtn.2022.10.001

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

Mol Ther Nucleic Acids. 2022 Oct 7:30:311-322. doi: 10.1016/j.omtn.2022.10.001. eCollection 2022 Dec 13.

Authors

Katerina-Marina Pilala¹, Maria-Alexandra Papadimitriou¹, Konstantina Panoutsopoulou¹, Petros Barbarigos¹, Panagiotis Levis², Georgios Kotronopoulos², Konstantinos Stravodimos², Andreas Scorilas¹, Margaritis Avgeris^{1

3}

Affiliations

¹ Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, 15771 Athens, Greece.
² First Department of Urology, "Laiko" General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece.
³ Laboratory of Clinical Biochemistry - Molecular Diagnostics, Second Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, 11527 Athens, Greece.

Abstract

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 performed using tumor relapse and progression as clinical endpoints 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 expression. Lower methylation of MIR145 core promoter was associated 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.

Keywords: DNA methylation; MT: Non-coding RNAs; bladder tumors; epigenetics; miRNA; prognosis; pyrosequencing; tumor progression; urothelial bladder carcinoma.