MP49-10 KNOCKDOWN OF GLYCOPROTEIN-130 INHIBITS BLADDER CANCER PROGRESSION AND MIGRATION

Abstract

You have accessJournal of UrologyBladder Cancer: Basic Research III1 Apr 2015MP49-10 KNOCKDOWN OF GLYCOPROTEIN-130 INHIBITS BLADDER CANCER PROGRESSION AND MIGRATION Darryl T. Martin, Jill M. Steinbach, Marcia A. Wheeler, Cayce B. Nawaf, W. Mark Saltzman, and Robert M. Weiss Darryl T. MartinDarryl T. Martin More articles by this author , Jill M. SteinbachJill M. Steinbach More articles by this author , Marcia A. WheelerMarcia A. Wheeler More articles by this author , Cayce B. NawafCayce B. Nawaf More articles by this author , W. Mark SaltzmanW. Mark Saltzman More articles by this author , and Robert M. WeissRobert M. Weiss More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.514AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Seventy-five percent of bladder cancer patients in the United States have noninvasive disease at initial diagnosis. Although, Bacillus Calmette-Guerin (BCG) is the most effective adjuvant agent for treating non-muscle invasive bladder cancer, the response to BCG is unpredictable. Therefore, alternative treatments are needed. Glycoprotein-130 (GP130) is a transmembrane protein which is central to a number of signal transduction pathways involved in tumor growth/progression. Our goal is to target and degrade GP130 with small interfering RNAs (siRNAs). GP130 siRNA will be encapsulated in our previously developed chitosan functionalized nanoparticle (NP) system. Using a bladder cancer mouse model we will determine if knocking down GP130 expression has a potential role in decreasing tumor growth/progression. METHODS GP130 expression was determined in human bladder cancer specimens on a tissue microarray (TMA) by immunohistochemistry. In vitro, cell viability and cell migration, as affected by down-regulation of GP130, were assessed using a tetrazolium colorimetric assay and a scratch assay, respectively. Down-regulation of GP130 expression was achieved with chitosan-NP encapsulating GP130 siRNA (NP-siGP130-CH) and controls such as untreated (PBS), chitosan NP vehicle (NP-CH), and chitosan-NP encapsulating scrambled siRNA (NP-siSC-CH) were used. Foxn1 nu/nu mice were subcutaneously injected with 5X106 UM-UC-3 bladder cancer cells and then randomly divided into 3 groups: PBS, NP-CH or NP-siGP130-CH. RESULTS In a human bladder cancer TMA, GP130 expression was significantly higher in high grade bladder cancer specimens (2.40 +/- 0.18 relative units) than in low grade cancer specimens (1.67 +/- 0.16 relative units). Furthermore, more aggressive human bladder cancer cell lines (UM-UC-3 and TCC sup) had a higher GP130 expression than a more differentiated bladder cancer cell line (RT4). When human bladder cancer cells were treated with GP130 siRNA, there was a 60% decrease in cell viability. In addition, the cells treated with GP130 siRNA only migrated at half the rate as the cells that received the controls. Xenograft mouse bladder tumors treated with NP-siGP130-CH were significantly smaller than tumors receiving either PBS or NP-CH controls at day 7 (41%, 38%), 11 (65%, 60%), and 14 (75%, 60%), respectively. CONCLUSIONS We have shown that GP130 expression is higher in high grade than low grade human bladder cancers and that GP130 plays a role in bladder cancer migration in vitro and in cancer progression in an in vivo bladder cancer mouse model. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e606 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Darryl T. Martin More articles by this author Jill M. Steinbach More articles by this author Marcia A. Wheeler More articles by this author Cayce B. Nawaf More articles by this author W. Mark Saltzman More articles by this author Robert M. Weiss More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...