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.

Clinical significance and effect of MTDH/AEG-1 in bladder urothelial cancer: a study based on immunohistochemistry, RNA-seq, and in vitro verification

“…The mean age was 61.62 years for the BUC cases and 52.43 years for the normal bladder cases. Histological sections were stained with hematoxylin and eosin (H&E) and were used to estimate the histological grade and pathologic stage 23,24. The 56 normal controls were removed from normal bladder tissues adjacent to neoplastic lesions and were confirmed from the H&E-stained slides as normal bladder tissues without cancer cells.…”

Predictive Markers for Malignant Urothelial Transformation in Balkan Endemic Nephropathy: A Case–Control Study

“…The results presented here suggest that the concentration of survivin is significantly higher in the plasma and urine of BEN patients. Previous articles concerning the expression of surviving in UC tissue specimens of BEN patients reported increased immunohistochemical expression of survivin as the most prominent marker of cancer of urothelial cells in BEN [ 22 , 25 , 26 ]. By exploring the Kaplan–Meier survival curves it was documented that increased survivin expression has a significantly shorter time for disease progression and development of metastases when compared to patients with normal survivin expression [ 28 ].…”

“…Vascular endothelial growth factor is a pro-angiogenic molecule and an important prognostic marker in UC. Our previous analyses concerned with the expression of both angiogenic growth factors and their receptors revealed that only VEGFR1 could be a significant discriminating factor between cancers of urothelial cells in BEN and non-BEN cancers [ 25 ]. The expression and concentration of VEGF and its receptor (VEGFR) in BEN patients was not significantly different from the controls ( Table 2 ).…”

“…With regard to the significant prediction of UC in BEN patients and the previous results concerning the immunohistochemical expression of proteomic tumor markers in UC tissue specimens of BEN patients [ 21 , 22 , 25 ], the primary aim of the current study is to assess a potential predictive significance of proteomic markers, such as survivin, p53 protein, angiogenetic growth factor (VEGF), VEGF receptor (VEGFR1), insulin-like growth factor (IGF I),IGF I receptor (IGF-1R), IGF-binding protein (IGFBP5), tumor marker (TF)/CD142, circulating soluble Fas (APO1) receptor and neopterin in plasma and urine of BEN patients with no signs of UC. It is followed by the analysis of their urinary /plasma ratio to find a potential local predictive influence and by the analysis of their urinary level by creatinine ratio to predict the staging/severity of a patient’s chronic kidney disease.…”

“…The disorders associated with stimulated proliferation and/or deregulated programmed cell death are important in the process of carcinogenesis. The disorders at the cellular level may refer to altered expression of tumor-suppressor proteins and a reduced expression of proteins or enzymes involved in apoptosis [ 21 , 22 ]. Progressive transformation of normal epithelial cell via premalignant into a malignant epithelial cell phenotype is a cascade which often involves the action of tumor promoters and mitogens.…”