You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology I (PD37)1 Sep 2021PD37-06 LATROPHILIN-3 AS A KEY DOWNSTREAM EFFECTOR OF THE ANDROGEN RECEPTOR INDUCES UROTHELIAL TUMORIGENESIS Takuro Goto, Yuki Teramoto, Yujiro Nagata, Guiyang Jiang, Taichi Mizushima, Satoshi Inoue, Hiroki Ide, George Netto, and Hiroshi Miyamoto Takuro GotoTakuro Goto More articles by this author , Yuki TeramotoYuki Teramoto More articles by this author , Yujiro NagataYujiro Nagata More articles by this author , Guiyang JiangGuiyang Jiang More articles by this author , Taichi MizushimaTaichi Mizushima More articles by this author , Satoshi InoueSatoshi Inoue More articles by this author , Hiroki IdeHiroki Ide More articles by this author , George NettoGeorge Netto More articles by this author , and Hiroshi MiyamotoHiroshi Miyamoto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002047.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: We and others have indicated that androgen receptor (AR) signaling plays a critical role in urothelial cancer outgrowth. Meanwhile, our DNA microarray data suggest that latrophilin-3 (LPHN3), one of latrophilins 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. The present study aims to determine the functional role of LPHN3 in urothelial carcinogenesis. METHODS: We determined the expression of LPHN3 in 145 bladder tumors and paired normal bladder tissues (by immunohistochemistry) as well as in human normal urothelial SVHUC sublines stably expressing wild-type AR or vector only (by RT-PCR and western blot). We then assessed the effects of ligand (e.g. LTX, FLRT3) treatment on neoplastic/malignant transformation of SVHUC-derived cells, as well as bladder tumor development in C57BL/6 mice, induced by chemical carcinogens (e.g. MCA, BBN). RESULTS: Immunohistochemistry showed that LPHN3 was positive in 52% (47% 1+, 5% 2+) of tumors, which was significantly (P=0.049) higher than in non-neoplastic urothelial tissues [37% (all 1+)], and that LPHN3 positivity in non-muscle-invasive tumors was associated with the risk of tumor recurrence after transurethral surgery (P=0.051). The level of LPHN3 expression was higher in SVHUC-AR cells than in AR-negative SVHUC-vector cells. In addition, significant induction in the LPHN3 expression by LTX or FLRT3 treatment was seen in SVHUC, whereas LPHN3 knockdown via shRNA virus infection in SVHUC-AR resulted in considerable induction or reduction of the expression of the proteins positively (e.g. cleaved caspase-3) or negatively (e.g. Bcl-2, Bcl-xL), respectively, associated with apoptosis. Chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of LPHN3 in SVHUC-derived cells. The in vitro transformation assay showed that LTX and FLRT3 induced the MCA-mediated oncogenic activity in both SVHUC-AR and SVHUC-vector cells, while the inhibitory effect of LPHN3 knockdown on the neoplastic transformation was observed in MCA-SVHUC-AR cells. LTX/FLRT3 also significantly accelerated the development of bladder tumors in BBN-treated female mice. CONCLUSIONS: These findings suggest that LPHN3, which is activated in bladder tumors as a key downstream effector of the AR, promotes urothelial tumorigenesis. Accordingly, LPHN3 inhibition, along with AR inactivation, has the potential of being an effective chemopreventive approach for urothelial cancer. Source of Funding: Ferring Research Institute © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e657-e657 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takuro Goto More articles by this author Yuki Teramoto More articles by this author Yujiro Nagata More articles by this author Guiyang Jiang More articles by this author Taichi Mizushima More articles by this author Satoshi Inoue More articles by this author Hiroki Ide More articles by this author George Netto More articles by this author Hiroshi Miyamoto More articles by this author Expand All Advertisement Loading ...
Read full abstract