The splicing factor PTBP1 promotes expression of oncogenic splice variants and predicts poor prognosis in patients with non-muscle invasive bladder cancer.

Purpose: Non-muscle invasive bladder cancer (NMIBC) is a malignant disease characterized by high heterogeneity, which corresponds to dysregulated gene expression and alternative splicing (AS) profiles. Bioinformatics analyses of splicing factors potentially linked to bladder cancer progression identified the heterogeneous nuclear ribonucleoprotein I (i.e. PTBP1) as candidate. This study aimed at investigating whether PTBP1 expression associates with clinical outcome in NMIBC patients. Experimental Design: A cohort of 152 patients presenting primary NMIBC (pTa-pT1) was enrolled. Primary NMIBCs were assessed for PTBP1 expression by immunohistochemistry (IHC) and the results were correlated with clinical data using Kaplan-Meier curves and Cox regression analyses. Cell proliferation and survival assays were performed to assess the function of PTBP1. Furthermore, the impact of PTBP1 on the AS pattern of specific bladder cancer-related genes was investigated in cancer cell lines and in patient's specimens. Results: Public datasets querying highlighted a positive correlation between PTBP1 expression and NMIBC progression, which was then confirmed by IHC analysis. High PTBP1 expression was associated with worse clinical outcome in terms of incidence of tumor relapse and survival in NMIBC patients. Interestingly, down-regulation of PTBP1 in bladder cancer cell lines affected pro-survival features. Accordingly, PTBP1 modulated AS of bladder cancer-related genes in cell lines and patient's specimens. Conclusion(s): PTBP1 expression correlates with disease progression, poor prognosis and worse survival in NMIBC patients. Down-regulation of PTBP1 expression affects pro-survival features of bladder cancer cells and modulates AS of genes with relevance for bladder cancer, suggesting its role as outcome-predictor in this disease.

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