Overexpression of BMAL-1 is related to progression of urothelial carcinoma in arsenic exposure area

Abstract

Background: 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.

Methods: Ninety-nine tumor tissue samples were retrospectively collected along with their respective clinical data. Immunohistochemistry was employed to assess the expression of each protein.

Results: 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.

Conclusions: 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.

Keywords: Arsenic; Aurora kinase A; BMAL-1; GSK-3β; Urothelial Carcinoma.