Loss of DAB2IP expression in human urothelial carcinoma is associated with poorer recurrence-free survival.

Abstract

The purpose of this study is to investigate the clinical relevance of deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/DAB2) interacting protein (DAB2IP) expression in human urothelial carcinoma (UC). We studied DAB2IP protein expression by immunohistochemistry in 130 UCs (90 of the bladder and 40 of the upper urinary tract) and 79 adjacent normal tissues and assessed its prognostic value in terms of recurrence-free and progression-free survival in superficial bladder UC. Twelve human UC cell lines were examined for DAB2IP messenger RNA (mRNA) and protein expression using quantitative RT-PCR and western blotting. Selected cell lines were used to study the effect of treatment with chromatin-modifying agents (5-aza-2'-deoxycytidine, Trichostatin A, or both) on DAB2IP expression. Of 90 bladder tumors, 50 (56%) and, of 40 upper tract UC, 11 (28%) were positive for DAB2IP immunostaining (bladder cancer versus upper tract UC, p=0.003). In 65 superficial cases of bladder cancer loss of DAB2IP, expression was significantly associated with decreased recurrence-free survival (p=0.046), but not with progression-free survival. Most human urothelial cancer cell lines consistently express DAB2IP mRNA and protein, without any relation to S-phase kinase protein expression. After treatment with either 5-aza-2'-deoxycytidine or Trichostatin A or both, the low DAB2IP-expressing bladder cancer cell lines BFTC905 and BFTC909 showed increased DAB2IP mRNA expression. DAB2IP protein levels are higher in bladder cancer than in upper tract UC and in superficial bladder cancer. This is associated with longer recurrence-free survival. Epigenetic regulation of DAB2IP protein appears to play an important role in human urothelial carcinoma.