MP36-20 DEFINING THE MOLECULAR DRIVERS OF HIGH-GRADE NON-INVASIVE UROTHELIAL CARCINOMA OF THE BLADDER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research I1 Apr 2015MP36-20 DEFINING THE MOLECULAR DRIVERS OF HIGH-GRADE NON-INVASIVE UROTHELIAL CARCINOMA OF THE BLADDER Haiping Zhou, Yan Liu, Herbert Lepor, Moon-shong Tang, Chuanshu Huang, and Xue-Ru Wu Haiping ZhouHaiping Zhou More articles by this author , Yan LiuYan Liu More articles by this author , Herbert LeporHerbert Lepor More articles by this author , Moon-shong TangMoon-shong Tang More articles by this author , Chuanshu HuangChuanshu Huang More articles by this author , and Xue-Ru WuXue-Ru Wu More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.748AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES High-grade non-invasive urothelial carcinoma of the bladder (HG-NIUCB) is a highly enigmatic entity that carries a high risk of progression to the invasive stage. The molecular and genetic underpinning of HG-NIUCB remains unclear, thus presenting a significant challenge in clinical management. This study employs second-generation genetically engineered mouse modeling to create a HG-NIUCB model, helping define its molecular drivers and provide an in vivo platform for investigating its mechanism(s) of progression. METHODS A human-relevant mutant of fibroblast growth factor receptor 3 (FGFR3-S249C) was engineered in transgenic mice such that its expression in bladder epithelium is triggered upon doxycycline treatment. Additionally, a compound mouse line was created that expressed not only the FGFR3-S249C mutant but also a Simian virus large T antigen. Parallel studies were performed by transfecting UroTsa, an SV40T antigen-immortalized human urothelial cell line with the FGFR3-S248C mutant. The phenotypic and molecular alterations were examined using histopathology, Real-time PCR, Western blotting, cell cycle analysis, immunofluorescence and immunohistochemistry. RESULTS Urothelium-specific and inducible expression of the FGFR3-S249C mutant in adult mice resulted in an increased expression of mitogenic signals such as phosphorylated AKT and MAPK but did not elicit urothelial proliferation or tumorigenesis. A compensatory tumor barrier was observed in FGRF3-S249C-expressing urothelial cells in the form of p53 and RB1 pathway activation, as the possible cause of the lack of tumorigenicity for FGFR3-S249C. Interestingly, functional inactivation of p53 and RB1 by urothelial expression of SV40T in FGFR3-S249C-expressing cells led to the formation of exclusively HG-NIUCB that bears strong resemblance to the human counterpart. An identical collaborative effect in tumor promotion was observed in UroTsa cell line transfected with the FGFR3-S249C mutant. CONCLUSIONS Despite the prevalence of FGFR3 mutations in human bladder cancer, our results suggest that cooperative genetic events are needed to render FGFR3 mutations tumorigenic. A combination of FGFR3 mutations and p53/RB pathway deficiency may be a new biomarker set for HG-NIUCB and inhibition of FGFR3 mutation or its downstream signaling pathway may be of therapeutic value in controlling this important but elusive urothelial carcinoma variant. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e437 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Haiping Zhou More articles by this author Yan Liu More articles by this author Herbert Lepor More articles by this author Moon-shong Tang More articles by this author Chuanshu Huang More articles by this author Xue-Ru Wu More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...