MP58-17 THE CONTRIBUTION OF HGF-MET-MMP1 SIGNALING IN BLADDER CANCER INVASION, AND MET INHIBITOR AS A POTENTIAL THERAPEUTIC OPTION FOR INVASIVE BLADDER CANCER

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2018MP58-17 THE CONTRIBUTION OF HGF-MET-MMP1 SIGNALING IN BLADDER CANCER INVASION, AND MET INHIBITOR AS A POTENTIAL THERAPEUTIC OPTION FOR INVASIVE BLADDER CANCER Tomoya Fukawa, Kei Daizumoto, Tomoharu Fukumori, Masayuki Takahashi, and Hiro-omi Kanayama Tomoya FukawaTomoya Fukawa More articles by this author , Kei DaizumotoKei Daizumoto More articles by this author , Tomoharu FukumoriTomoharu Fukumori More articles by this author , Masayuki TakahashiMasayuki Takahashi More articles by this author , and Hiro-omi KanayamaHiro-omi Kanayama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.1849AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Muscle-invasive bladder cancer (MIBC) has an especially poor prognosis, and clarification of the mechanism of MIBC invasion is urgent to discover appropriate treatment strategies and to improve the prognosis of patients with MIBC. Our previous report showed that co-culture of bladder cancer cells with mesenchymal cells which highly expressed HGF stimulated the invasion ability of bladder cancer cells. The aim of this study was to elucidate the underlying mechanisms of the increased invasion ability of bladder cancer cells by co-culture with mesenchymal cells, clarify the contribution of HGF-MET signaling pathway to bladder cancer progression and find a new therapeutic option for MIBC. METHODS We analyzed the expression of MET in the bladder cancer cell lines by Western blotting. Using the cell lines which highly expressed MET, we examined the effects of Cabozantinib on their proliferation and invasion abilities by using MTT and Matrigel invasion assays. To investigate the biological function of HGF-MET signaling, we analyzed gene expression profiles of bladder cancer cells that were cultivated with/without the effects of the MET inhibitor, Cabozantinib (XL184). We also examined the effects of MMP-1 depletion on invasion ability to clarify the importance of HGF-MET-MMP1 signaling in bladder cancer invasion. To verify our results with clinical samples, we checked the relationship between the expression of MET and MMP-1 by using TCGA data. RESULTS The expression of MET was high in four of five bladder cancer cell lines, and 5637 and T24 cells showed especially high protein expression of MET. The treatment with HGF stimulated cell proliferation and invasion of these cancer cells, whereas Cabozantinib inhibited those effects induced by HGF stimulation. To clarify the underlying mechanisms, we analyzed gene expression profiles by using microarray and revealed that the expression of MMP-1 was significantly elevated by HGF addition. We also confirmed that Cabozantinib suppressed the expression of MMP-1 which was induced by HGF addition in bladder cancer cells. Consistent with these results, we found the strong association between the expression of MET and MMP1 by using TCGA data. Furthermore, the depletion of MMP-1 dramatically suppressed the invasion ability of bladder cancer cells, suggesting that HGF contributes bladder cancer invasion by regulating the expressions of MMP-1 CONCLUSIONS The results of this study suggested that the blockade of HGF-MET-MMP1 signaling could be a potential therapeutic option and Cabozantinib is one of the potential molecules for the treatment of MIBC. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e779 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Tomoya Fukawa More articles by this author Kei Daizumoto More articles by this author Tomoharu Fukumori More articles by this author Masayuki Takahashi More articles by this author Hiro-omi Kanayama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...