Stojnev Slavica, Conic Irena, Ristic Petrovic Ana, Petkovic Ivan, Radic Milica, Krstic Miljan, Jankovic Velickovic Ljubinka
Center for Pathology, University Clinical Center Nis, 18000 Nis, Serbia.
Department of Pathology, Faculty of Medicine, University of Nis, 18000 Nis, Serbia.
Biomedicines. 2024 May 18;12(5):1123. doi: 10.3390/biomedicines12051123.
Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.
触发外源性凋亡途径的死亡受体信号传导和转化生长因子-β1（TGF-β1）在尿路上皮癌发生过程中起重要作用，二者之间存在复杂的相互作用。本研究的目的是评估死亡受体DR4、DR5和FAS以及TGF-β1免疫组化表达与膀胱尿路上皮癌（UBC）临床病理特征的相关性，并评估它们的预后意义。死亡受体表达的降低或缺失与肌层浸润性肿瘤显著相关，而非浸润性UBC通常保留死亡受体的表达，且二者相互紧密关联。DR4高表达是低级别肿瘤以及与接触已知致癌物相关的UBC的一个标志物。相反，TGF-β1与高肿瘤分级和晚期显著相关。DR4和FAS高表达表明总生存期更长。TGF-β1高表达预示预后较差，是UBC患者不良预后的独立预测因子。本研究揭示了UBC中死亡受体的表达谱及其与TGF-β1的可能联系，并表明FAS和TGF-β1高表达在UBC中具有独立的预后意义，鉴于包括靶向肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡途径在内的新型有效治疗方法的快速发展，这可能有助于破解UBC异质性之谜。
