title: Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder.
abstract: 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.
authors.affiliation: Department of Urology and Reproductive Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Koga
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawakami
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fujii
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Saito
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohtsuka
authors.forename: Aki
authors.initials: A
authors.lastname: Iwai
authors.forename: Noboru
authors.initials: N
authors.lastname: Ando
authors.forename: Touichiro
authors.initials: T
authors.lastname: Takizawa
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kageyama
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kihara
mesh_terms: 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
chemical_list: 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