Wu Yu-Jui, Chang Shu-Jyuan, Huang Yen-Shuo, Chai Chee-Yin
School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Int Urol Nephrol. 2025 Apr;57(4):1175-1187. doi: 10.1007/s11255-024-04320-1. Epub 2024 Dec 6.
Environmental exposure to arsenic has long been associated with various clinical and pathophysiological aspects of urothelial carcinoma (UC), although the role of arsenic in UC and its impact on circadian proteins, particularly BMAL-1, remains unestablished. Previous research suggests that arsenic upregulates Aurora kinase A (AURKA), subsequently inhibiting GSK-3β, which might lead to overexpression of BMAL-1; nevertheless, the underlying pathway and its clinical significance in UC with arsenic exposure have yet to be validated. This study focuses on two potential upstream regulators of BMAL-1, AURKA and GSK-3β.
Ninety-nine tumor tissue samples were retrospectively collected along with their respective clinical data. Immunohistochemistry was employed to assess the expression of each protein.
A positive relationship was observed between the expression levels of AURKA and BMAL-1 (p < 0.001), while negative correlations were noted between the expression levels of GSK-3β and AURKA (p < 0.001), and between GSK-3β and BMAL-1 (p = 0.003). Tissue samples exposed to arsenic exhibited significantly higher levels of AURKA (p < 0.001) and BMAL-1 (p < 0.001), a markedly lower expression of GSK-3β (p = 0.001), alongside a decreased survival status (p = 0.025) compared to non-exposed samples. Furthermore, patients with UC of higher tumor grade tended to show increased levels of AURKA (p < 0.001), BMAL-1 (p < 0.001), and decreased levels of GSK-3β (p < 0.001). Elevated expression of AURKA (p < 0.001) and BMAL-1 (p = 0.002), as well as reduced expression of GSK-3β (p = 0.003), were also associated with a decreased survival status.
This study highlights the differential expression of BMAL-1, AURKA, and GSK-3β in association with arsenic exposure and their significant impact on clinical and pathological features of UC. Moreover, BMAL-1, AURKA, and GSK-3β emerge as potential prognostic markers for UC in regions with arsenic exposure.
长期以来,环境砷暴露一直与尿路上皮癌(UC)的各种临床和病理生理方面相关,尽管砷在UC中的作用及其对昼夜节律蛋白,特别是BMAL-1的影响仍未明确。先前的研究表明,砷上调极光激酶A(AURKA),随后抑制糖原合成酶激酶-3β(GSK-3β),这可能导致BMAL-1的过表达;然而,在砷暴露的UC中其潜在途径及其临床意义尚未得到验证。本研究聚焦于BMAL-1的两个潜在上游调节因子,即AURKA和GSK-3β。
回顾性收集99份肿瘤组织样本及其各自的临床数据。采用免疫组织化学法评估每种蛋白的表达。
观察到AURKA和BMAL-1的表达水平呈正相关(p<0.001),而GSK-3β与AURKA的表达水平之间(p<0.001)以及GSK-3β与BMAL-1的表达水平之间呈负相关(p=0.003)。与未暴露样本相比,暴露于砷的组织样本中AURKA(p<0.001)和BMAL-1(p<0.001)水平显著更高,GSK-3β的表达明显更低(p=0.001),同时生存状况下降(p=0.025)。此外,肿瘤分级较高的UC患者往往表现出AURKA(p<0.001)、BMAL-1(p<0.001)水平升高,GSK-3β水平降低(p<0.001)。AURKA(p<0.001)和BMAL-1(p=0.002)表达升高以及GSK-3β表达降低(p=0.003)也与生存状况下降相关。
本研究强调了BMAL-1、AURKA和GSK-3β与砷暴露相关的差异表达及其对UC临床和病理特征的显著影响。此外,BMAL-1、AURKA和GSK-3β成为砷暴露地区UC的潜在预后标志物。