MP88-08 TR4 NUCLEAR RECEPTOR PROMOTES CLEAR CELL RENAL CELL CARCINOMA (CCRCC) VASCULOGENIC MIMICRY (VM) FORMATION AND METASTASIS VIA ALTERING THE MIR490-3P/VIMENTIN SIGNALS (2018)

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2018MP88-08 TR4 NUCLEAR RECEPTOR PROMOTES CLEAR CELL RENAL CELL CARCINOMA (CCRCC) VASCULOGENIC MIMICRY (VM) FORMATION AND METASTASIS VIA ALTERING THE MIR490-3P/VIMENTIN SIGNALS Jian Bai, Jinbo Chen, Xiaofu Qiu, ShuYuan Yeh, Linyi Hu, Jun Zeng, Yangke Cai, Gonghui Li, Edward M. Messing, Guosheng Yang, and Chawnshang Chang Jian BaiJian Bai More articles by this author , Jinbo ChenJinbo Chen More articles by this author , Xiaofu QiuXiaofu Qiu More articles by this author , ShuYuan YehShuYuan Yeh More articles by this author , Linyi HuLinyi Hu More articles by this author , Jun ZengJun Zeng More articles by this author , Yangke CaiYangke Cai More articles by this author , Gonghui LiGonghui Li More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Guosheng YangGuosheng Yang More articles by this author , and Chawnshang ChangChawnshang Chang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2928AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin(VIM) signals. METHODS We first studied a database in TCGA, including gene expression data from 606 primary ccRCC samples to examine the TR4 expression. To further confirm this clinical data in the various ccRCC cell lines (786-0, SW839 and Caki-1), we assayed TR4 expression and applied the Matrigel-coated Transwell invasion assay and 3D invasion assay to examine their invasion capacity. We then assayed its influences on the VM tube formation and cell invasion via altering the TR4 expression. To further dissect the molecular mechanism how TR4 could decrease the VIM expression, we first searched for potential TR4 response elements (TR4REs) on the VIM 5' promoter region using JASPAR database. We then applied the Chip-on in vivo binding assay to examine TR4 binding to these TR4REs. To verify how miR-490-3p can directly regulate VIM expression through targeting its 3'UTR, we identified some potential binding sites located on the 3'UTR of VIM-mRNA and applied the reporter assay with the pscheck2 vector carrying the wild type and mutant miRNA-target sites. To prove the above in vitro cell line data in the in vivo mouse model, we applied the orthotopic ccRCC xenograft mouse model. We generated stable clones of Caki-1 cells with luciferase expression with overexpressed TR4 and/or overexpressed miR-490-3p as well as a control, with 8 mice/group (1: Scr+luc; 2: oeTR4+luc; 3: oemi490-3p+luc; and 4: oeTR4+oemi490-3p+luc). Tumor progressions were evaluated via the non-invasive in vivo imaging system (IVIS). IHC staining from these ccRCC xenograft tumors were also evaluated. RESULTS Here we provide the first preclinical study data showing that TR4 may play positive roles in RCC VM formation and metastasis. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3'UTR of VIM-mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. CONCLUSIONS Our results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1200 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Jian Bai More articles by this author Jinbo Chen More articles by this author Xiaofu Qiu More articles by this author ShuYuan Yeh More articles by this author Linyi Hu More articles by this author Jun Zeng More articles by this author Yangke Cai More articles by this author Gonghui Li More articles by this author Edward M. Messing More articles by this author Guosheng Yang More articles by this author Chawnshang Chang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...