Goto Takuro, Teramoto Yuki, Nagata Yujiro, Miyamoto Hiroshi
Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
Discov Oncol. 2024 Sep 13;15(1):440. doi: 10.1007/s12672-024-01324-2.
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) 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 the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.
新出现的证据表明，雄激素受体（AR）信号传导在男性主导的尿路上皮癌发病机制及其生长过程中起关键作用。同时，促胃液素释放肽受体（LPHNs）是一类已知可与蜘蛛毒液latrotoxin（LTX）结合的G蛋白偶联受体，在肿瘤疾病中仍基本未被研究。本研究旨在确定LPHN3（由ADGRL3基因编码）与AR信号传导相关联在膀胱癌进展中的功能作用。在AR阳性的膀胱癌细胞系中，双氢睾酮显著增加了ADGRL3和LPHN3的表达水平，而染色质免疫沉淀分析显示AR与ADGRL3启动子区域结合。用LPHN3配体（如α-LTX、FLRT3）处理可诱导膀胱癌细胞系中ADGRL3的表达以及细胞活力。相比之下，通过shRNA病毒感染敲低LPHN3可显著降低这些细胞的活力和迁移能力。经尿道切除标本的免疫组织化学进一步显示LPHN3与AR表达之间存在强相关性。此外，肌肉浸润性膀胱肿瘤中LPHN3阳性作为一个独立的预后指标，与根治性膀胱切除术后疾病进展和疾病特异性死亡的风险显著升高相关。这些发现表明LPHN3作为AR的下游效应器发挥作用并促进膀胱癌的生长。
