MP45-01 HIGH ALDO-KETO REDUCTASE 1C1 EXPRESSION IN METASTATIC BLADDER CANCER CELLS ASSOCIATED WITH INVASIVE POTENTIAL AND DRUG RESISTANCE

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2015MP45-01 HIGH ALDO-KETO REDUCTASE 1C1 EXPRESSION IN METASTATIC BLADDER CANCER CELLS ASSOCIATED WITH INVASIVE POTENTIAL AND DRUG RESISTANCE Ryuji Matsumoto, Masumi Tsuda, Takashige Abe, Satoru Maruyama, Kunihiko Tsuchiya, Naoto Miyajima, Nobuo Shinohara, and Shinya Tanaka Ryuji MatsumotoRyuji Matsumoto More articles by this author , Masumi TsudaMasumi Tsuda More articles by this author , Takashige AbeTakashige Abe More articles by this author , Satoru MaruyamaSatoru Maruyama More articles by this author , Kunihiko TsuchiyaKunihiko Tsuchiya More articles by this author , Naoto MiyajimaNaoto Miyajima More articles by this author , Nobuo ShinoharaNobuo Shinohara More articles by this author , and Shinya TanakaShinya Tanaka More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1499AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The objective of this study were to investigate the genetic changes responsible for bladder cancer metastasis, using orthotopic metastatic mouse model, and to find new therapeutic targets of invasive bladder cancer. METHODS Human UM-UC-3 bladder cancer cells were generated to express firefly luciferase 2 and red fluorescent protein tdTomato (UM-UC-3-tdTomato-luc2). Subsequently, we developed an orthotopic xenograft nude mouse model of bladder cancer by inoculating UM-UC-3-tdTomato-luc2 cells through a urethral catheter into the mouse bladder. We then performed bioluminescent imaging (BLI) to noninvasively monitor the growth of bladder tumors in their orthotopic sites. Two mice underwent autopsy after confirmation of lung or liver metastases using BLI. The primary and metastatic tumors were excised and plated on tissue culture dishes to generate bladder, lung, liver, and bone sublines. To examine the role of metastasis-related genes in bladder cancer, we then performed comparative microarray analyses of gene expression, and analyzed gene expression changes in bladder vs. lung, bladder vs. liver and bladder vs. bone. RESULTS Among the 8 genes commonly up-regulated in metastatic sublines compared to bladder cells by our microarray analysis, the expression of aldo-keto reductase 1C1 (AKR1C1) was especially up-regulated. Furthermore, AKR1C1 was significantly upregulated in the 3 metastatic sublines by qRT-PCR and immunoblot analysis. In clinical samples, we observed increased expression of AKR1C1 in human metastatic tissues compared with the corresponding primary bladder cancer tissues by qRT-PCR and immunohistochemistry analysis. Knockdown of AKR1C1 using small interfering RNA downregulated expression levels of Rac1, phosphorylated Src, and phosphorylated FAK, accompanied by reduced invasive ability. Overexpression of AKR1C isoforms, including AKR1C1, has been demonstrated to be associated with drug resistance in various cancers. UM-CU-3 metastatic cells were more resistant to cisplatin than were UM-UC-3 wild-type cells, and AKR1C1 inhibitor flufenamic acid reversed cisplatin resistance in these cells. CONCLUSIONS We found that AKR1C1 was up-regulated both in metastatic bladder cancer cells using an orthotopic mouse model and in metastatic sites of human surgical specimens. Our results demonstrate the role of AKR1C1 in regulating bladder cancer metastasis and drug resistance; therefore, AKR1C1 is a potential target for effective treatment of invasive bladder cancer. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e535 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryuji Matsumoto More articles by this author Masumi Tsuda More articles by this author Takashige Abe More articles by this author Satoru Maruyama More articles by this author Kunihiko Tsuchiya More articles by this author Naoto Miyajima More articles by this author Nobuo Shinohara More articles by this author Shinya Tanaka More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...