title: Survivin nuclear labeling index: a superior biomarker in superficial urothelial carcinoma of human urinary bladder.
abstract: The caspase family proteases are key proapoptotic proteins while the inhibitor of apoptosis proteins (IAP) prevent apoptosis by antagonizing the caspases or other key proapoptotic proteins. Limited studies of IAPs suggested their deregulation contributed to urothelial neoplasia. However, the expression status and biologic or prognostic significance of the caspase and IAP family proteins in urothelial neoplasms is not clear. In the present study, we first systematically evaluated the expression profile of the major apoptosis regulators, including caspases (CASP3, 6, 7, 8, 9, 10, and 14), IAPs (survivin/BIRC5, CIAP1, CIAP2, XIAP, and LIVIN), APAF1, SMAC, and BCL2, as well as proliferation markers Ki67 and PHH3, in Ta/T1 human urinary bladder urothelial carcinomas and normal urothelium samples by immunohistochemistry. The analysis showed that survivin/BIRC5 nuclear labeling index (BIRC5-N), but not cytoplasmic staining, was the only apoptotic marker which correlated significantly with tumor grade, stage, and patient outcome. We further analyzed the prognostic value of BIRC5-N in 101 Ta/T1 urinary bladder urothelial carcinomas by univariate analysis, which showed that BIRC5-N as well as the more classical prognosticators (stage, grade, and Ki67 index) were of prognostic significance. However, multivariate analysis by Cox proportional hazard regression demonstrated BIRC5-N was a stronger prognosticator than tumor grade, stage, and Ki67 labeling index. BIRC5-N index of 8% or more predicted unfavorable disease-specific survival (relative risk (RR)=6.6, 95% confidence interval=1.6-26.7, P=0.0080) as well as progression-free survival (RR=4.4, 95% confidence interval=1.3-14.6, P=0.0151). We conclude that BIRC5-N is a superior biologic and prognostic marker for Ta/T1 urothelial carcinomas of urinary bladder.
authors.affiliation: Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Yin
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.forename: Yutao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Zeng
authors.forename: Xueqin
authors.initials: X
authors.lastname: Chen
authors.forename: Yongtao
authors.initials: Y
authors.lastname: He
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.forename: Qiao
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000737:chemistry*; D049109:Cell Proliferation; D015331:Cohort Studies; D003593:Cytoplasm / Q000737:chemistry; D005069:Evaluation Studies as Topic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D053208:Kaplan-Meier Estimate; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis*; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D009367:Neoplasm Staging; D016017:Odds Ratio; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D013997:Time Factors; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D019459:Urothelium / Q000737:chemistry* / Q000473:pathology
chemical_list: C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin