Latrophilins as downstream effectors of the androgen receptor induce bladder cancer progression

You have accessJournal of UrologyCME1 Apr 2023MP14-20 LATROPHILINS AS DOWNSTREAM EFFECTORS OF THE ANDROGEN RECEPTOR INDUCE BLADDER CANCER PROGRESSION Takuro Goto, Yuki Teramoto, Masato Yasui, Guiyang Jiang, Yujiro Nagata, and Hiroshi Miyamoto Takuro GotoTakuro Goto More articles by this author , Yuki TeramotoYuki Teramoto More articles by this author , Masato YasuiMasato Yasui More articles by this author , Guiyang JiangGuiyang Jiang More articles by this author , Yujiro NagataYujiro Nagata More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003234.20AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We and others have indicated that androgen receptor (AR) activity is strongly associated with urothelial cancer outgrowth. Meanwhile, our DNA microarray data suggest that latrophilin-3 (LPHN3), one of latrophilins (LPHNs) that are a group of the G-protein-coupled receptor where a spider venom latrotoxin (LTX) is known to bind, represents a downstream target of AR in bladder cancer cells. However, the involvement of LPHNs in neoplastic diseases has not been documented. The present study aimed to determine the functional role of LPHNs, including LPHN1, LPHN2, and LPHN3, in the progression of bladder cancer. METHODS: We determined the levels of LPHN expression in 145 bladder tumors (by immunohistochemistry) as well as in human bladder cancer lines (by RT-PCR/western blot). We then assessed the effects of ligand (e.g. LTX, FLRT3) treatment, as well as silencing of each LPHN via shRNA virus infection, on the growth of bladder cancer cells. RESULTS: Bladder tumors showed immunoreactivity for LPHN1 (86%), LPHN2 (66%), and LPHN3 (52%). The positive rates for LPHN1 (92%/95% vs. 69%/78%, p<0.001/p=0.004) and LPHN2 (77%/81% vs. 46%/55%, p<0.001/p=0.002) were significantly higher in high-grade/muscle-invasive tumors than in low-grade/non-muscle-invasive tumors, respectively. In addition, LPHN1 (HR=3.026, 95% CI=1.008-9.084, p=0.048) or LPHN3 (HR=2.314, 95% CI=1.123-4.771, p=0.023) positivity in muscle-invasive tumors showed significance for disease-specific mortality even in a multivariate setting. In AR-positive bladder cancer lines, androgen treatment considerably increased the expression levels of LPHN1, LPHN2, and LPHN3. Chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of each LPHN in bladder cancer cells. Meanwhile, treatment with LTX or FLRT3 induced the expression of each LPHN. MTT assay then showed that LTX or FLRT3 increased the cell viability of bladder cancer lines, while knockdown of LPHN1, LPHN2, or LPHN3 reduced it. Similarly, induction by LTX/FLRT3 treatment and inhibition by LPHN1/LPHN2/LPHN3 knockdown in the ability of cell migration were seen. CONCLUSIONS: LPHNs, as downstream effectors of the AR, are thus likely to be activated in some bladder cancers, which may result in the promotion of tumor growth. Moreover, immunohistochemistry for LPHNs may be useful for predicting tumor progression, particularly in those with muscle-invasive disease. Accordingly, LPHN inhibition, along with AR inactivation, has the potential of being an effective therapeutic approach for urothelial cancer. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e190 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takuro Goto More articles by this author Yuki Teramoto More articles by this author Masato Yasui More articles by this author Guiyang Jiang More articles by this author Yujiro Nagata More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement PDF downloadLoading ...