Latrophilin-3 as a downstream effector of the androgen receptor induces bladder cancer progression

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. alpha-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.