Role of Latrophilin-1 and Latrophilin-2 as Downstream Effectors of Androgen Receptor Signaling in Urothelial Tumorigenesis.

BACKGROUND

Accumulating evidence indicates a critical role of androgen receptor (AR) in the pathogenesis of male-dominant urothelial cancer. Meanwhile, the functions of latrophilins (LPHNs), a subfamily of G protein-coupled receptors, remain largely uncharacterized in neoplastic conditions.

AIMS: To determine the functional role of LPHN1 and LPHN2 in association with AR signaling in urothelial tumorigenesis.

METHODS AND

RESULTS

AR overexpression in immortalized human normal urothelial SVHUC cells or androgen treatment in SVHUC-AR cells markedly increased the expression levels of LPHN1 and LPHN2. Chromatin immunoprecipitation assay demonstrated that AR could bind to the promoter regions of their encoded genes, ADGRL1 and ADGRL2. In SVHUC-AR cells exposed to a chemical carcinogen 3-methylcholanthrene to induce neoplastic transformation, shRNA-mediated knockdown of LPHN1 or LPHN2 significantly reduced their oncogenic activity, as measured by the ability of the resultant cells to form colonies and migrate. Immunohistochemistry in surgical specimens further revealed significantly higher levels of LPHN1 and LPHN2 expression in non-muscle-invasive bladder tumors than in adjacent non-neoplastic urothelial tissues.

CONCLUSIONS

The present findings suggest that LPHN1 and LPHN2 function as downstream mediators of AR signaling and promote urothelial tumorigenesis.