Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.
Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.
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发表时间：
2003-11
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通讯作者：
F. Koga;S. Kawakami;Y. Fujii;K. Saito;Yukihiro Ohtsuka;A. Iwai;N. Ando;T. Takizawa;Y. Kageyama;K. Kihara
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作者：
F. Koga;S. Kawakami;Y. Fujii;K. Saito;Yukihiro Ohtsuka;A. Iwai;N. Ando;T. Takizawa;Y. Kageyama;K. Kihara
目的p63被认为在包括尿路上皮在内的复层上皮细胞的正常发育和分化中发挥作用。我们最近报道，p63表达受损是高级别浸润性尿路上皮癌的共同特征，并与β-连环素降低有关。基于这些事实，我们认为p63表达受损与尿路上皮肿瘤的生物学侵袭性有关。我们还评估了尿路上皮蛋白(UP)III的表达，以探讨p63表达缺失与尿路上皮终末分化之间的可能联系。实验设计采用免疫组织化学方法检测75例高级别浸润性膀胱癌标本中p63、β-连环蛋白和UPⅢ的表达。半定量P63的表达，并与病理参数、β-连环蛋白和UPⅢ的表达以及肿瘤特异性生存期进行比较。结果p63低表达与肿瘤转移分期高(P=0.0004)、淋巴结转移高(P=0.013)、β-连环素表达低(P=0.003)有关。单因素分析显示，p63低表达、肿瘤分期和淋巴结状况与预后不良显著相关(P=0.0005)，而β-连环素表达降低与预后无关。多因素分析显示，p63的表达与肿瘤的临床分期和淋巴结状况无关(P=0.074)。UP III的表达仅限于部分p63阴性的癌细胞，甚至包括间变性癌细胞。结论p63表达受损是高级别浸润性尿路上皮癌生物学侵袭性的特征。此外，p63表达的缺失是uP III表达的先决条件。我们的数据表明，p63在肿瘤进展和尿路上皮肿瘤的生化终末分化中起关键作用。
PURPOSE p63 is proposed to play roles in normal development and differentiation of stratified epithelia including urothelium. We recently reported that impaired p63 expression is a common feature of high-grade invasive urothelial carcinomas and associates with reduced beta-catenin. On the basis of these facts, we proposed that impaired p63 expression contributes to biological aggressiveness of urothelial neoplasms. Uroplakin (UP) III expression was also evaluated to investigate a possible association between loss of p63 expression and terminal urothelial differentiation. EXPERIMENTAL DESIGN Expression of p63, beta-catenin, and UP III was immunohistochemically analyzed in 75 cystectomy specimens of high-grade invasive bladder carcinoma. p63 expression was semiquantified and compared with pathological parameters, expression of beta-catenin and UP III, and cancer-specific survival. RESULTS Lower p63 expression was significantly associated with higher Tumor-Node-Metastasis (TNM) stage (P = 0.0004), lymph-node metastasis (P = 0.013), and reduced beta-catenin expression (P = 0.003). By univariate analysis, lower p63 expression, along with TNM stage and lymph-node status, were significantly associated with a poor prognosis (P = 0.0005), whereas reduced beta-catenin was not. By multivariate analysis, the prognostic effect of p63 expression was independent of TNM stage and lymph-node status with marginal statistical significance (P = 0.074). UP III expression was restricted to a subset of p63-negative carcinoma cells, including even anaplastic carcinoma cells. CONCLUSIONS Impaired p63 expression characterizes biological aggressiveness of high-grade invasive urothelial carcinomas. Moreover, loss of p63 expression is a prerequisite for UP III expression. Our data suggest that p63 plays critical roles in tumor progression and biochemical terminal differentiation of urothelial neoplasms.