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.