Koga Fumitaka, Kawakami Satoru, Fujii Yasuhisa, Saito Kazutaka, Ohtsuka Yukihiro, Iwai Aki, Ando Noboru, Takizawa Touichiro, Kageyama Yukio, Kihara Kazunori
Department of Urology and Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Clin Cancer Res. 2003 Nov 15;9(15):5501-7.
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.
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.
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.
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.
p63被认为在包括尿路上皮在内的复层上皮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一个常见特征，且与β-连环蛋白减少有关。基于这些事实，我们提出p63表达受损促成了尿路上皮肿瘤的生物学侵袭性。还评估了uroplakin（UP）III的表达，以研究p63表达缺失与尿路上皮终末分化之间的可能关联。
对75例高级别浸润性膀胱癌的膀胱切除标本进行p63、β-连环蛋白和UP III表达的免疫组织化学分析。对p63表达进行半定量分析，并与病理参数、β-连环蛋白和UP III的表达以及癌症特异性生存率进行比较。
较低的p63表达与较高的肿瘤-淋巴结-转移（TNM）分期（P = 0.0004）、淋巴结转移（P = 0.013）以及β-连环蛋白表达降低（P = 0.003）显著相关。单因素分析显示，较低的p63表达以及TNM分期和淋巴结状态与预后不良显著相关（P = 0.0005），而β-连环蛋白减少则不然。多因素分析显示，p63表达的预后作用独立于TNM分期和淋巴结状态，具有边际统计学意义（P = 0.074）。UP III表达局限于p63阴性癌细胞的一个子集，甚至包括间变性癌细胞。
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表达缺失是UP III表达的先决条件。我们的数据表明，p63在尿路上皮肿瘤的肿瘤进展和生化终末分化中起关键作用。
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