Pro- and antiapoptotic markers in upper tract urothelial carcinoma associated with Balkan endemic nephropathy

Abstract

The role of aristolochic acid in the etiology of Balkan endemic nephropathy (BEN) and associated upper-tract urothelial carcinoma (UTUC) has been recently confirmed. The aim of this study was to determine apoptosis-related marker(s) specific for BEN-associated UTUC. Present investigation included 105 patients with UTUC, 44 from BEN region and 61 control tumors. Altered expression of Survivin was more often present in BEN UTUC with high grade and solid growth (P < 0.005; P < 0.05) than in control tumors. Significantly lower expression of proapoptotic marker Bax was found in BEN tumors with high grade, high stage, necrosis, and without metaplastic change (P < 0.05; 0.05; 0.05; 0.05) compared to control tumors with the same features. Group (BEN-related/control), stage, growth pattern, and caspase 3 activity were significantly associated with the expression of Bax (P = 0.002, 0.034, 0.047, 0.028, resp.,). This investigation identifies Bax as specific marker of BEN-associated UTUC. Decrease of pro-apoptotic protein Bax together with alteration of Survivin may be indicative for specific disturbances of intrinsic apoptotic pathway in UTUC arising in endemic areas.

Keywords: Balkan endemic nephropathy; Bax; Bcl-2; Caspase 3; Fas; Survivin; apoptosis; upper tract urothelial carcinoma.

Figure 1

The representative immunohistochemical staining of apoptotic markers in BEN-associated urothelial carcinoma, with strong nuclear Survivin activity in high grade (a) and tumors with solid growth (b), diffuse Bax cytoplasm expression (c), membranous Fas staining in nonmetaplastic BEN-related tumors (d). Rarely Bcl-2 positive tumor cells (e). Caspase 3 expression in a high-grade tumor (f) (original magnification: x400).