Epithelial-to-mesenchymal transition based diagnostic and prognostic signature markers in non-muscle invasive and muscle invasive bladder cancer patients

Abstract

Background: Diagnostic and prognostic significance of epithelial-to-mesenchymal transition (EMT) associated biomarkers are evaluated in a cohort of NMIBC (non-muscle invasive bladder cancer) and MIBC (muscle invasive bladder cancer) patients.

Methods and results: Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining were carried out in 100 tumor specimens (59 NMIBC and 41 MIBC). The expressions of the epithelial marker, mesenchymal markers and EMT-activating transcription factors (EMT-ATFs) were determined at transcriptome and protein level followed by their statistical associations with clinicohistopathological variables of the patients. Transcriptomic expression analysis showed statistical relevance of tumor stage with increased Twist and Zeb-1; tumor type with reduced E-cadherin and increased Snail; and smoking/tobacco chewing status (S/TC) of patients with increased N-cadherin and Snail in NMIBC patients. Tumor grade with reduced message E-cadherin, gain of N-cadherin, Snail, Twist and Zeb-1; patients' age with reduced E-cadherin and Twist gain; and tumor type with increased message N-cadherin exhibited associations in MIBC patients. Protein expression analysis identified statistical relevance of tumor grade with nuclear gain of Snail and Twist; and nuclear gain of Slug with S/TC status of NMIBC patients. Novel gain of membranous Vimentin deduced association with patients' age in MIBC patients. Survival analysis identified novel Vimentin as the positive predictor of short progression free survival (PFS) and short overall survival (OS) in MIBC patients. Study established altered EMT profile as the independent negative predictor of short recurrence free survival (RFS) in NMIBC patients and positive predictor of short PFS and OS in MIBC patients.

Conclusions: EMT associated biomarkers could provide diagnostic and prognostic risk stratification and hence could be of importance in the clinical management of bladder cancer patients.

Keywords: Biomarkers; Bladder cancer; Diagnosis and prognosis; Epithelial-to-mesenchymal transition; Survival probabilities.