230 INHIBITION OF PROSTATE SPECIFIC MEMBRANE ANTIGEN GENE-EXPRESSION IS MEDIATED BY TMPRSS2:ERG GENE FUSION IN VCAP PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2010230 INHIBITION OF PROSTATE SPECIFIC MEMBRANE ANTIGEN GENE-EXPRESSION IS MEDIATED BY TMPRSS2:ERG GENE FUSION IN VCAP PROSTATE CANCER CELLS Pravin Rao, Lihong Yin, and Warren Heston Pravin RaoPravin Rao Lakewood, OH More articles by this author , Lihong YinLihong Yin Cleveland, OH More articles by this author , and Warren HestonWarren Heston Cleveland, OH More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.288AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is over-expressed in prostatic adenocarcinoma (CaP). Levels of PSMA expression have been correlated with aggressive disease and risk of early recurrence after radical prostatectomy (RP). Studies have shown that a significant fraction of CaP's harbor a signature gene fusion between the androgen-responsive TMPRSS2 gene and transcription factors in the ETS family – most commonly ERG. The TMPRSS2-ERG fusion is likely the cause for over-expression of ERG in CaP. PSMA, unlike ERG, is negatively regulated by androgen. Elucidation of the relationship between TMPRSS2 gene fusions and PSMA expression could reveal mechanisms to alter PSMA expression and disease course. The purpose of this investigation was to determine whether PSMA gene expression could be regulated by the TMPRSS2-ERG fusion in prostate cancer cells. METHODS VCaP cells (which harbor the TMPRSS2:ERG fusion) and LNCaP cells (which do not) were incubated with vehicle or the androgen-receptor antagonist flutamide prior to treatment with synthetic androgen R1881. In addition, transfection of siRNA against human ERG was performed to create ERG knockdown in VCaP cells. Reverse transcription (RT) PCR as well as real-time RT PCR were used to detect and quantify transcription of ERG, TMPRSS2:ERG, PSMA, and androgen receptor (AR) genes. Using the comparative threshold cycles method, the quantification of these transcripts was performed, and expression was compared in various androgen-treated and untreated VCaP and LNCaP cells. RESULTS After 24-hour androgen treatment, ERG and TMPRSS2-ERG mRNA level were increased in VCaP cells and unchanged in LNCaP cells. PSMA and androgen receptor (AR) mRNA level were dramatically decreased in VCaP cells and modestly decreased in LNCaP cells. Treatment with the androgen antagonist flutamide partially restored PSMA and AR expression in androgen-treated VCaP cells. Knocking down ERG by siRNA in VCaP cells enhances PSMA mRNA expression both in the presence and absence of R1881, while it has minimal change of AR mRNA in VCaP-ERG knock down cells. CONCLUSIONS Down-regulation of PSMA in androgen-treated VCaP cells appears partially mediated by the TMPRSS2:ERG gene fusion. Since PSMA has been associated with aggressive disease and early biochemical failure after RP, further elucidation of the relationship between TMPRSS2 gene fusions and PSMA could reveal potential novel targets for treatment of prostate cancer. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e90 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pravin Rao Lakewood, OH More articles by this author Lihong Yin Cleveland, OH More articles by this author Warren Heston Cleveland, OH More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...