MP39-11 ESTROGEN RECEPTOR Β PROMOTES RENAL CELL CARCINOMA MALIGNANCY AND TKI RESISTANCE VIA REGULATING LNCRNA AND CIRCRNA ASSOCIATED CERNA NETWORK

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP39)1 Sep 2021MP39-11 ESTROGEN RECEPTOR Β PROMOTES RENAL CELL CARCINOMA MALIGNANCY AND TKI RESISTANCE VIA REGULATING LNCRNA AND CIRCRNA ASSOCIATED CERNA NETWORK Yixi Hu, Jie Ding, Junfei Gu, Zhenwei Han, Wenbiao Ren, Edward M. Messing, Chawnshang Chang, Jean V. Joseph, and Shuyuan Yeh Yixi HuYixi Hu More articles by this author , Jie DingJie Ding More articles by this author , Junfei GuJunfei Gu More articles by this author , Zhenwei HanZhenwei Han More articles by this author , Wenbiao RenWenbiao Ren More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Chawnshang ChangChawnshang Chang More articles by this author , Jean V. JosephJean V. Joseph More articles by this author , and Shuyuan YehShuyuan Yeh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002054.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Kidney cancer accounts for at least 3% of malignant diseases, and the incidence and mortality appear to be rising. Recent studies indicated that the estrogen receptor beta (ERβ), but not the ER alpha, could affect the progression of renal cell carcinoma (RCC), however, its downstream signals remain to be further elucidated. METHODS: Human 786-O, A498, ACHN, and Caki-1 RCC cell lines were used. The RNAs of 10 nM E2 treated and shERβ transfected 786-O cells were isolated for RNA-Seq and non-coding RNA analysis. Invasion assays were performed using the matrigel transwell and 3D invasion assays. The q-PCR analysis and western blot were performed to evaluate the RNA and the protein expressions. HOTAIR promoter was constructed into the pGL3 for luciferase assays. Protein-DNA complexes were detected by Chromatin immunoprecipitation (ChIP) assay. RNA pull-down assays were performed to detect the binding of putative miRNAs. A preclinical xenograft mouse RCC model was used to validate ERβ signal-promoted ceRNA network. RESULTS: RNAseq data of RCC patients were retrieved from the TCGA database and analysis results showed high expressions of ERβ and its down-stream signals were associated with advanced stages and poor prognosis in RCC patients. Mechanism dissection revealed that targeting ERβ with ERβshRNA and stimulating the transactivation of ERβ with 17β-estradiol or environmental endocrine disrupting chemicals, resulted in altering the lncRNA HOTAIR expression. The ERβ-modulated HOTAIR can function via antagonizing several miRNAs (miR-138, -200c, -204, or -217) to impact various oncogenes, including ADAM9, CCND2, EZH2, VEGFA, VIM, ZEB1, and ZEB2, to promote RCC invasion. In addition, we found ERβ can suppress the expression of the circular RNA, circATP2B1, which then led to a reduced miR-204-3, increased fibronectin 1 (FN1) expression, and enhanced RCC cell invasion. Our results further showed that the expression levels of those ERβ regulated long non-coding RNAs (lncRNAs), circRNAs, and miRNAs could predict the malignancy or TKI resistance of RCC. CONCLUSIONS: We provide evidence that expression levels of ERβ and ERβ-regulated CeRNA network could be used to predict metastasis and overall survival in RCC patients. The identification of the ERβ-lncRNA or circRNA regulated signal pathways may provide physicians with new biomarkers and/or therapeutic targets to better control RCC progression in the future. Source of Funding: This work was partially supported by URMC Urology Department Research Fund and George Whipple H. Professorship Endowment © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e708-e709 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yixi Hu More articles by this author Jie Ding More articles by this author Junfei Gu More articles by this author Zhenwei Han More articles by this author Wenbiao Ren More articles by this author Edward M. Messing More articles by this author Chawnshang Chang More articles by this author Jean V. Joseph More articles by this author Shuyuan Yeh More articles by this author Expand All Advertisement Loading ...