MP31-09 IDENTIFICATION OF A RETRO-TRANSPOSON DERIVED GENE ASSOCIATED WITH PROGRESSION TO NEUROENDOCRINE PROSTATE CANCER. (2014)

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2014MP31-09 IDENTIFICATION OF A RETRO-TRANSPOSON DERIVED GENE ASSOCIATED WITH PROGRESSION TO NEUROENDOCRINE PROSTATE CANCER. Shusuke Akamatsu, Alexander Wyatt, Dong Lin, Summer Lysakowski, Fan Zhang, Soojin Kim, Ladan Fazli, Himisha Beltran, Mark Rubin, Amina Zoubeidi, Yuzhuo Wang, Colin Collins, and Martin Gleave Shusuke AkamatsuShusuke Akamatsu More articles by this author , Alexander WyattAlexander Wyatt More articles by this author , Dong LinDong Lin More articles by this author , Summer LysakowskiSummer Lysakowski More articles by this author , Fan ZhangFan Zhang More articles by this author , Soojin KimSoojin Kim More articles by this author , Ladan FazliLadan Fazli More articles by this author , Himisha BeltranHimisha Beltran More articles by this author , Mark RubinMark Rubin More articles by this author , Amina ZoubeidiAmina Zoubeidi More articles by this author , Yuzhuo WangYuzhuo Wang More articles by this author , Colin CollinsColin Collins More articles by this author , and Martin GleaveMartin Gleave More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.918AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The treatment of castration resistant prostate cancer has dramatically improved with the recent development of potent androgen receptor (AR) pathway inhibitors. However, stronger AR pathway inhibition appears to be driving resistance mechanisms that are independent of the AR axis, the most recognized of which is neuroendocrine prostate cancer (NEPC). To date, few genes have been associated with progression to NEPC. We developed a patient-derived xenograft model of NEPC trans-differentiation: a hormone-naïve adenocarcinoma that upon AR-blockade initially regresses, but rapidly relapses as NEPC. In this study, we carried out longitudinal expression profiling of xenograft tumors during the trans-differentiation process to identify genes associated with tumor cell survival post-castration and the development NEPC. METHODS Gene profiling of xenografts collected at different time points during the trans-differentiation were compared to data sets of human NEPC. Immunohistochemistry was performed using clinical NEPC samples. Loss of function studies were carried out using siRNA and shRNA in cell growth (WST-8), invasion (Boyden chamber) and migration (scratch) assays. RESULTS We identified a retro-transposon derived gene, Paternally Expressed 10 (PEG10), to be highly expressed during the early trans-differentiation stage and also in clinical NEPC. We confirmed at the protein level that PEG10 is up-regulated post-castration and further significantly elevated in terminal NEPC. PEG10 was highly expressed within NEPC foci of clinical samples. Knockdown of PEG10 in prostate cancer (PC) cells induced apoptosis and G0/G1 arrest, and also attenuated invasion and migration. We found PEG10 knockdown inhibited invasion and migration induced by TGF-β, and modulated response of the cells to TGF-β, resulting in decreased phosphorylation of Smad2 and Smad3, decrease in SBE4 luciferase reporter activity, and inhibition of Snail and Zeb1 induction. Collectively, these data show that PEG10 promotes PC cell growth, and also cooperates with TGF-β to promote invasion and migration of PC cells, conferring aggressive phenotype to these cells. CONCLUSIONS PEG10 is a gene associated both with growth and invasion of NEPC, and is a potential novel therapeutic target for the treatment of NEPC. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e325 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Shusuke Akamatsu More articles by this author Alexander Wyatt More articles by this author Dong Lin More articles by this author Summer Lysakowski More articles by this author Fan Zhang More articles by this author Soojin Kim More articles by this author Ladan Fazli More articles by this author Himisha Beltran More articles by this author Mark Rubin More articles by this author Amina Zoubeidi More articles by this author Yuzhuo Wang More articles by this author Colin Collins More articles by this author Martin Gleave More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...