Sphingosine-1-phosphate receptor 1 (S1PR1) expression in non-muscle invasive urothelial carcinoma: Association with poor clinical outcome and potential therapeutic target

Aim: Sphingosine-1-phosphate receptor 1 (S1PR1) promotes tumour cell survival, invasion, anti-apoptosis, metastasis and radio/chemo-resistance in various cancers. However, the expression pattern and prognostic implications of S1PR1 in urothelial carcinoma remain unclear and thus were addressed here. Methods: Tissue microarrays composed of 395 initially diagnosed and transurethral resected urothelial carcinomas of the urinary bladder were immunostained for S1PR1 and phosphor-signal transducer and activator of transcription 3 (pSTAT3). S1PR1 expression was analysed according to clinicopathological features, expression of several anti-apoptosis/proliferation-related markers and patient's survival. Results: S1PR1 positivity was observed in 45.3% of urothelial carcinomas. Among patients with non-muscle invasive urothelial carcinoma (NMIC), S1PR1 positivity was associated with higher grade (P < 0.001), higher subepithelial invasive component (P = 0.006), lower papillary component (P = 0.002), presence of metastasis (P = 0.042) and high cancer-specific death (P < 0.001). S1PR1 expression was correlated with pSTAT3 (P < 0.001), survivin (P = 0.008) and Ki-67 (P < 0.001) expression. S1PR1 positivity predicted a shorter cancer-specific survival (CSS) in NMICs (P < 0.001) and stage T1/high grade (T1HG) tumours (P = 0.002). The Cox multivariate model was composed of S1PR1, survivin, lymphovascular invasion and age, and C-index was 0.781. S1PR1 positivity was correlated with shorter CSS in p53-positive T1HG carcinoma (P = 0.003) in contrast to p53-negative T1HG carcinoma (P = 0.205). In p53-overexpressing NMIC, S1PR1 was the only variable of the survival model and the C-index was 0.719. Conclusions: S1PR1 expression was associated with unfavourable clinicopathological features and the expression of several anti-apoptosis/proliferation-related markers in urothelial carcinoma. S1PR1 serves as an independent predictor of cancer-specific death in NMIC. The model including S1PR1 showed highly accurate prediction for CSS in NMIC patients regardless of the modality of adjuvant therapy. (C) 2015 Elsevier Ltd. All rights reserved.