Abstract
Bladder cancer is the fifth most common malignancy in the world and represents the second most common cause of death among genitourinary tumors. Current prognostic parameters such as grade and stage cannot predict with certainty the long-term outcome of bladder cancer, and as a result there is a pressing need to identify markers that may predict tumor behavior. Earlier we identified the adipocyte fatty acid-binding protein (A-FABP), a small-molecular-mass fatty acid-binding protein that functions by facilitating the intracellular diffusion of fatty acids between cellular compartments as a putative marker of progression based on a limited study of fresh bladder urothelial carcinomas (UCs) (Celis, J. E., Ostergaard, M., Basse, B., Celis, A., Lauridsen, J. B., Ratz, G. P., Andersen, I., Hein, B., Wolf, H., Orntoft, T. F., and Rasmussen, H. H. (1996) Loss of adipocyte-type fatty acid binding protein and other protein biomarkers is associated with progression of human bladder transitional cell carcinomas. Cancer Res.56, 4782-4790). Here we have comprehensively examined the protein expression profiles of a much larger sample set consisting of 153 bladder specimens (46 nonmalignant biopsies, 11 pTa G1, 40 pTa G2, 10 pTa G3, 13 pT1 G3, 23 pT2-4 G3, and 10 pT2-4 G4) by gel-based proteomics in combination with immunohistochemistry (IHC) using a peptide-based rabbit polyclonal antibody that reacts specifically with this protein. Proteomic profiling showed a striking down-regulation of A-FABP in invasive lesions, a fact that correlated well with immunohistochemical analysis of the same samples. The IHC results were confirmed by using a tissue microarray (TMA) containing 2,317 samples derived from 1,849 bladder cancer patients. Moreover, we found that the altered expression of A-FABP in invasive UCs is not due to deregulated expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a trans-activator of A-FABP. Taken together, these results provide evidence that deregulation of A-FABP may play a role in bladder cancer progression and suggest that A-FABP could have a significant prognostic value in combination with other biomarkers.
Highlights
Bladder cancer is the fifth most common malignancy in the world and represents the second most common cause of death among genitourinary tumors
The adipocyte fatty acid-binding protein (A-fatty acid-binding proteins (FABPs))-specific rabbit polyclonal antibody was prepared by Eurogentec, and the antibody against peroxisome proliferators-activated receptors (PPARs)␥ was purchased from Santa Cruz Biotechnology (Santa Cruz, CA)
We presented here gel-based proteomic evidence showing that loss of A-FABP expression in bladder carcinomas occurs mainly in invasive urothelial carcinomas (UCs), an observation that was confirmed by IHC analysis of a tissue microarray (TMA) containing 2,317 samples derived from 1,849 bladder cancer patients (Table II)
Summary
Bladder cancer is the fifth most common malignancy in the world and represents the second most common cause of death among genitourinary tumors Current prognostic parameters such as grade and stage cannot predict with certainty the long-term outcome of bladder cancer, and as a result there is a pressing need to identify markers that may predict tumor behavior. Bladder cancer is the second most common genitourinary tumor and the fourth most common solid malignancy in Denmark, with an incidence of 1,200 –1,300 patients per year and a mortality rate of ϳ300. The most reliable prognostic factors for recurrence and progression are grading and staging These parameters, cannot predict with certainty the long-term outcome of the disease, and as a result it is important to devise strategies to identify biomarkers that may predict tumor behavior and clinical outcome. The abbreviations used are: UC, urothelial carcinoma; pRB, retinoblastoma gene; A-FABP, adipocyte-type fatty acid-binding protein; PPAR, peroxisome proliferator-activated receptor; IHC, immunohistochemistry; TMA, tissue microarray; 2D, two dimensional; PPRE, peroxisome-proliferator-responsive element; RXR, retinoid X receptor
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