Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.
OBJECTIVE
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.


METHODS
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.
Koga
Fumitaka
F
Department of Urology and Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Kawakami
Satoru
S
Fujii
Yasuhisa
Y
Saito
Kazutaka
K
Ohtsuka
Yukihiro
Y
Iwai
Aki
A
Ando
Noboru
N
Takizawa
Touichiro
T
Kageyama
Yukio
Y
Kihara
Kazunori
K
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015653:Cystectomy; D003598:Cytoskeletal Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D060171:Uroplakin III; D019459:Urothelium / Q000473:pathology; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C554660:UPK3A protein, human; D060171:Uroplakin III; D051176:beta Catenin