Relationship between high microRNA-200C expression and the risk of death from disease in muscle-invasive urothelial carcinoma of the bladder.

Abstract

279 Background: Bladder cancer represents both a common and highly morbid disease with limited tools for prognostication. Recently molecular studies have led to promising targets to inform disease behavior, including microRNAs (miRNA). miRNAs are non-coding RNAs, with widespread effects on cellular function. Our group has demonstrated that the miR200 family members play an integral role in epithelial to mesenchymal transition (EMT) via an inverse relationship with ZEB1 and a direct relationship with E-cadherin. EMT is seen as a necessary step for invasion and metastasis, however, studies have indicated a significant role for mesenchymal to epithelial transition (MET) to drive proliferation after cells have reached metastatic locations. Members of the miR200 family have been shown to induce MET and we hypothesize that miR200c, as a surrogate marker for MET, and will predict disease survival in muscle invasive urothelial carcinoma (MIUC). Methods: A clinically diverse sample set was obtained consisting of 101 unique specimens upon which real-time PCR miRNA analysis was performed. Regression tree analysis and best-fit modeling was used to establish the most discriminating relative miR200c expression level to predict disease specific survival. Fisher exact test was carried out to compare clinical variables, Kaplan-Meier estimate of survival distribution based on miR200c expression and univariate log-rank test was used to compare survival distributions between groups. Multivariate analysis was done via the proportional hazards model. A p-value of <0.05 was considered significant for all statistical analyses. Results: Patients with high miRNA200c had significantly more deaths (69 vs. 47%). In multivariable analysis of patients with MIUC miR200c expression was associated with the highest risk of death (RR 2.7). Lymph node involvement (RR 2.0) and age > 65yrs (RR 2.4) were also strong predictors of survival. High miR200c had lower median survival for all patients (59 vs 16 months; p = 0.039) and those with MIUC (41 vs 8 months; p = 0.0004). Conclusions: High miR200c expression is associated with a higher risk of death from bladder cancer in patients with muscle invasive disease.