Protective role of mineralocorticoid receptor signaling in urothelial tumorigenesis

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothe-lial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcho-lanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The in vitro system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, com-pared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expres-sion of beta-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moder-ate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (P < 0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recur-rence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (P=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (P=0.025), compared with re-spective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.

Automated summary

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma were investigated in this study. It was found that MR can suppress the development of urothelial cancer. Furthermore, inhibiting MR expression or using MR antagonists increased the expression of beta-catenin, c-Fos, and N-cadherin, while decreasing the expression of E-cadherin. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.