Nagata Yujiro, Matsukawa Takuo, Goto Takuro, Teramoto Yuki, Jiang Guiyang, Fujimoto Naohiro, Miyamoto Hiroshi
Department of Pathology & Laboratory Medicine, University of Rochester Medical Center Rochester, NY 14642, USA.
James P. Wilmot Cancer Institute, University of Rochester Medical Center Rochester, NY 14642, USA.
Am J Cancer Res. 2023 Feb 15;13(2):408-418. eCollection 2023.
The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial 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-methylcholanthrene (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 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, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of β-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% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.
盐皮质激素受体（MR）在人尿路上皮癌中的表达状况及其生物学意义尚不清楚。本研究旨在确定MR在尿路上皮癌发生发展中的功能作用。在暴露于化学致癌物3-甲基胆蒽（MCA）的人正常尿路上皮SVHUC细胞中，我们评估了天然MR配体醛固酮和3种MR拮抗剂（包括螺内酯、依普利酮和依沙贝隆）以及通过shRNA病毒感染敲低MR对其肿瘤性/恶性转化的影响。致癌物刺激系统显示，醛固酮和抗盐皮质激素分别显著预防和促进了SVHUC细胞的肿瘤转化。同样，与对照亚系相比，SVHUC细胞中MR敲低显著诱导了MCA介导的肿瘤转化。此外，MR敲低或拮抗剂处理导致β-连环蛋白、c-Fos和N-钙黏蛋白表达增加，E-钙黏蛋白表达减少。同时，已知具有抗雄激素活性的螺内酯反而抑制了稳定表达野生型雄激素受体的SVHUC亚系的肿瘤转化，表明其通过雄激素受体途径起主要作用。手术标本的免疫组织化学检测发现，78例非侵袭性膀胱肿瘤中有77例（98.7%；23.1%弱/1+、42.3%中度/2+和33.3%强/3+）检测到MR信号，这显著低于相邻非肿瘤性尿路上皮组织（100%；20.5% 2+和79.5% 3+）（<0.001）。此外，与各自的对照组相比，MR高表达（2+/3+）肿瘤的女性患者经尿道手术后疾病复发风险略低（=0.068），而MR高表达/糖皮质激素受体高表达肿瘤的所有患者疾病复发风险显著降低（=0.025）。这些发现表明，MR信号传导在尿路上皮肿瘤发生中起抑制作用。
