Goto Takuro, Yasui Masato, Teramoto Yuki, Nagata Yujiro, Mizushima Taichi, Miyamoto Hiroshi
Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, New York, USA.
James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.
Mol Carcinog. 2024 Oct;63(10):1847-1854. doi: 10.1002/mc.23783. Epub 2024 Jun 24.
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.
新出现的证据表明，雄激素受体（AR）信号传导在男性为主的尿路上皮癌发病机制中起关键作用。同时，促胃液素释放肽受体（LPHNs）是一类已知可与蜘蛛毒液latrotoxin结合的G蛋白偶联受体，在肿瘤疾病中基本未被研究。本研究旨在确定LPHN3（由ADGRL3基因编码）与AR信号传导相关在尿路上皮肿瘤发生中的功能作用。在人正常尿路上皮SVHUC细胞中，AR过表达和雄激素处理显著增加了ADGRL3/LPHN3的表达水平，而染色质免疫沉淀试验显示AR与ADGRL3启动子区域结合。在暴露于化学致癌物3-甲基胆蒽的SVHUC或SVHUC-AR细胞中，在肿瘤/恶性转化过程中通过配体（如α-latrotoxin、FLRT3）处理激活LPHN3或通过shRNA病毒感染敲低LPHN3分别诱导或降低致癌活性。在经N-丁基-N-（4-羟基丁基）亚硝胺处理的雌性小鼠中，注射α-latrotoxin或FLRT3加速了膀胱肿瘤的发展。手术标本的免疫组织化学进一步显示，与相邻正常尿路上皮组织相比，非肌层浸润性膀胱肿瘤中LPHN3的表达显著升高，这与经尿道切除术后疾病复发风险略高（p = 0.051）相关。此外，这些肿瘤中LPHN3和AR的阳性呈强相关。这些发现表明，LPHN3作为AR的下游效应物发挥作用并促进尿路上皮肿瘤发生。
