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

Eur J Cancer. 2015 Sep;51(14):1937-45. doi: 10.1016/j.ejca.2015.07.021. Epub 2015 Jul 31.

Abstract

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.

Keywords: Cancer-specific survival; Non-muscle invasive urothelial carcinoma; Prediction; Prognosis; Sphingosine-1-phosphate receptor 1; Survivin; p53.

MeSH terms

  • Aged
  • Apoptosis
  • Biomarkers, Tumor / analysis*
  • Carcinoma / chemistry*
  • Carcinoma / mortality
  • Carcinoma / secondary
  • Carcinoma / surgery
  • Cell Proliferation
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Grading
  • Phosphorylation
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Receptors, Lysosphingolipid / analysis*
  • Risk Factors
  • STAT3 Transcription Factor / analysis
  • Sphingosine-1-Phosphate Receptors
  • Tissue Array Analysis
  • Urinary Bladder Neoplasms / chemistry*
  • Urinary Bladder Neoplasms / mortality
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / surgery
  • Urothelium / chemistry*
  • Urothelium / pathology
  • Urothelium / surgery

Substances

  • Biomarkers, Tumor
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Sphingosine-1-Phosphate Receptors