title: Sphingosine-1-phosphate receptor 1 (S1PR1) expression in non-muscle invasive urothelial carcinoma: Association with poor clinical outcome and potential therapeutic target.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: damul37@naver.com.
authors.forename: Heounjeong
authors.initials: H
authors.lastname: Go
authors.affiliation: Biomedical Knowledge Engineering Laboratory, Seoul National University, School of Dentistry, Seoul 110-749, Republic of Korea. Electronic address: childcom@snu.ac.kr.
authors.forename: Pil-Jong
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea. Electronic address: junarplus@chol.com.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: yongcho@amc.seoul.kr.
authors.forename: Yong Mee
authors.initials: YM
authors.lastname: Cho
authors.affiliation: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 110-746, Republic of Korea. Electronic address: kekim23@naver.com.
authors.forename: Kyungeun
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Pathology, Green Cross Laboratories, Yongin-si, Kyunggi-do 446-770, Republic of Korea. Electronic address: as-watchman@hanmail.net.
authors.forename: Bong-Hee
authors.initials: BH
authors.lastname: Park
authors.affiliation: University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: kooossi@hanmail.net.
authors.forename: Ja Yoon
authors.initials: JY
authors.lastname: Ku
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D010766:Phosphorylation; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D049349:Receptors, Lysosphingolipid / Q000032:analysis*; D012307:Risk Factors; D050796:STAT3 Transcription Factor / Q000032:analysis; D000081025:Sphingosine-1-Phosphate Receptors; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D019459:Urothelium / Q000737:chemistry* / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000081025:Sphingosine-1-Phosphate Receptors
keywords: Cancer-specific survival; Non-muscle invasive urothelial carcinoma; Prediction; Prognosis; Sphingosine-1-phosphate receptor 1; Survivin; p53