MP88-16 THE DOWNREGULATION AND TUMOR SUPPRESSIVE FUNCTION OF RASAL2 IN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2018MP88-16 THE DOWNREGULATION AND TUMOR SUPPRESSIVE FUNCTION OF RASAL2 IN RENAL CELL CARCINOMA Ke Hui, Kaijie Wu, Jer-Tsong Hsieh, and Dalin He Ke HuiKe Hui More articles by this author , Kaijie WuKaijie Wu More articles by this author , Jer-Tsong HsiehJer-Tsong Hsieh More articles by this author , and Dalin HeDalin He More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2936AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Patients with renal cell carcinoma (RCC) often develop resistance to anti-vascular drug and eventually succumb to disease. However, the underlying molecular mechanism of drug resistance remains poorly understood. In this study, we demonstrated that RASAL2, a RAS GTPase activating protein (RASGAP), played suppressive role in in RCC by targeting tumor angiogenesis. METHODS RCC and its paired normal kidney tissues were immunohistochemically stained for RASAL2 expression. Databases downloaded from TCGA or GEO were used to analyze the methylation status of RASAL2 and the correlation between RASAL2 and c-FOS or VEGFA in RCC tissues. In vitro, RASAL2 gain-function in 786-O cells or loss-function in ACHN cells were measured for the recruitment and tube formation of human umbilical vein endothelial cell (HUVEC) by HUVEC migration assay and tube formation assay, ELISA assay and western blot analysis. In vivo, subcutaneous xenografts in nude mice were used to detect tunorigenicity. Moreover, the expression of RASAL2, VEGFA and CD31 in RCC tissues and xenografts were detect by immunohistochemical (IHC) staining. RESULTS The expression of RASAL2 was downregulated in RCC tissues, and RASAL2 mRNA was inversely correlated with RASAL2 methylation or c-FOS mRNA or VEGFA mRNA in RCC tissues. Overexpression of RASAL2 in 786-O cells could inhibit the recruitment and tube formation of HUVECs, while RASAL2 knockdown (KD) in ACHN cells enhanced the recruitment and tube formation of HUVECs in vitro. Also, overexpression of RASAL2 could inhibit tumorigenecity of xenografts. Mechanistically, RASAL2 KD could enhance the phosphorylation of GSK3 and upregulate the expression of c-FOS and VEGFA. Furthermore, RASAL2 was inversely correlated with VEGFA and CD31 in tissues from human RCC specimens and xenografts. CONCLUSIONS RASAL2 was downregulated in RCC tissues, which could lead to tumor angiogenesis via p-GSK3/c-FOS/VEGFA signaling pathway. Therefore, RASAL2 could be a potential target to prevent patients with RCC from resistance to anti-vascular therapy. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1203-e1204 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Ke Hui More articles by this author Kaijie Wu More articles by this author Jer-Tsong Hsieh More articles by this author Dalin He More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...