o:1668 Analiza ekspresije transformišućeg faktora rasta beta i ćelijskih receptora smrti u urotelnom karcinomu mokraćne bešike i njihov prognostički značaj ǂThe ǂanalysis of expression of ransforming growth factor beta and cell death receptors in urothelial bladder cancer and their prognostic significance : doctoral dissertation sr Bladder cancer is the most frequent malignant tumor of the urinary tract. It represents a significant burden to the healthcare system due to necessity of lifelong cystoscopic controls, and management of recurrent disease. More than 90% of bladder cancers are urothelial carcinomas. Dysregulation of transforming growth factor beta (TGF- β) signaling pathways plays important role in tumor development and progression. Activation of TGF-β and cell death receptors involves common pathways in the activation of caspases and induction of apoptosis. The significance of immunohistochemical expression of TGF-β and death receptors in urothelial bladder cancer has not been fully elucidated. This study comprised 647 urothelial bladder cancers obtained by transurethral resection that were immunohistochemically analyzed to the expression of TGF-β1 and death receptors DR4, DR5, and FAS. The expression of Smad4, a protein with the central role in TGF-β canonical pathway signal transmission, and EZH2, an epigenetic regulator involved in TGF-β signalization, was also analyzed. Association assessment between the markers’ expression and clinicopathological parameters and follow-up data was performed. High TGF-β1 expression in urothelial cancer was significantly associated with high tumor grade and advanced stage, while the reduction/loss of death receptors’ expression correlated to muscle-invasive disease. High Smad4 expression was associated with tumor recurrence. Cancer-specific mortality was directly linked to high TGF-β1 and EZH2 expression, and inversely to DR4, FAS, and Smad4 expression. High TGF-β1 was associated with shorter overall survival of the patients, while high expression of DR4 and FAS in tumor cells correlated with less aggressive phenotype of the tumor, and longer overall survival. The present study identified the expression of TGF-β1, FAS, and EZH2 as independent prognostic factors in urothelial bladder cancer, where high TGF-β1 and EZH2 expression indicates shorter survival and poor prognosis, while high FAS receptor expression imparts protective aspect and is linked to longer overall survival. Further insight into knowledge about complex roles and significance of TGF-β and death receptors, as well as the analysis of their expression in urothelial bladder cancer, may have important implications for prognostic stratification of the patients and in deciding about their clinical management. Beleška o autoru: list 209;Bibliografija: listovi 176-208. Datum odbrane: 06.07.2020. Pathology 17631241 91552101 7547 91552100 17631241 2020-08-27T12:13:44.053Z 45 no 46 mentor Slavica 1981- Stojnev 2019 63 mentor Ljubinka 1960- Janković-Veličković 2019 63 predsednik komisije Miljan Krstić 2019 63 član komisije Dobrila Škodrić Radojević 2019 209 lista 8249146 http://phaidrabg.bg.ac.rs/o:1668 no yes 4 2020-08-27T12:13:44.320Z 70 Urotelni karcinom mokraćne bešike, transformišući faktor rasta beta,receptori smrti, imunohistohemija, ukupno preživljavanje, prognoza Urothelial bladder cancer, transforming growth factor beta, deathreceptors, immunohistochemistry, overall survival, prognosis 616.62-006.6:616-076-037(043.3) B520, B 200 1738 18A05 18A0518 2019