A-FABP, a candidate progression marker of human transitional cell carcinoma of the bladder, is differentially regulated by PPAR in urothelial cancer cells

Superficial pT1 bladder tumors are characterized by a high risk of recurrence and progression in grade and stage. Few studies provided evidence that loss or adipocyte-fatty acid binding protein (A-FABP) expression was associated with bladder cancer progression. A-FABP is a lipid binding protein playing a role in intracellular lipid transport and metabolism, as well as in signal transduction. We reported from bladder tumors that decrease of A-FABP transcript level significantly correlated to tumor stage and to histologic grade (p < 0.05). Namely, in poor prognosis high grade pT1 tumors there was a loss of A-FARP expression compared to good prognosis tumors suggesting that re-expression of A-FABP could be a therapeutic approach in early stage bladder cancer to prevent disease progression. We demonstrated for the first time that this marker is upregulated by Peroxisome Proliferator-Activated Receptor (PPAR) alpha, beta and gamma in T24 cells (derived from an undifferentiated grade III carcinoma) and only by PPAR beta in RT4 cells (derived from a well differentiated grade I papillary tumor). This effect occurred through a PPAR-dependent transcriptional mechanism without modifying mRNA stability and interestingly required de novo protein synthesis. Data as a whole suggest a prognostic significance of A-FABP in bladder cancer outcome and the potential utility of overexpression of this protein by PPAR agonists open up new perspectives in the treatment of bladder cancer. (C) 2008 Wiley-Liss, Inc.