Yin Wu, Chen Ni, Zhang Yutao, Zeng Hao, Chen Xueqin, He Yongtao, Wang Xiaojie, Zhou Qiao
Department of Pathology, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Mod Pathol. 2006 Nov;19(11):1487-97. doi: 10.1038/modpathol.3800675. Epub 2006 Aug 4.
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.
半胱天冬酶家族蛋白酶是关键的促凋亡蛋白，而凋亡抑制蛋白（IAP）通过拮抗半胱天冬酶或其他关键促凋亡蛋白来阻止细胞凋亡。对IAP的有限研究表明，它们的失调与尿路上皮肿瘤形成有关。然而，半胱天冬酶和IAP家族蛋白在尿路上皮肿瘤中的表达状态以及生物学或预后意义尚不清楚。在本研究中，我们首先通过免疫组织化学系统评估了主要凋亡调节因子的表达谱，包括半胱天冬酶（CASP3、6、7、8、9、10和14）、IAP（生存素/BIRC5、CIAP1、CIAP2、XIAP和LIVIN）、APAF1、SMAC和BCL2，以及增殖标志物Ki67和PHH3，在Ta/T1期人膀胱尿路上皮癌和正常尿路上皮样本中的表达情况。分析表明，生存素/BIRC5核标记指数（BIRC5-N）而非细胞质染色，是唯一与肿瘤分级、分期和患者预后显著相关的凋亡标志物。我们通过单因素分析进一步分析了BIRC5-N在Ta/T1期膀胱尿路上皮癌中的预后价值，结果表明BIRC5-N以及更经典的预后指标（分期、分级和Ki67指数）均具有预后意义。然而，Cox比例风险回归多因素分析表明，BIRC5-N是比肿瘤分级、分期和Ki67标记指数更强的预后指标。BIRC5-N指数为8%或更高预测不良的疾病特异性生存（相对风险（RR）=6.6，95%置信区间=1.6-26.7，P=0.0080）以及无进展生存（RR=4.4，95%置信区间=1.3-14.6，P=0.0151）。我们得出结论，BIRC5-N是膀胱Ta/T1期尿路上皮癌的一种优越的生物学和预后标志物。
