1304 DOWN-REGULATION OF ERG IN PROSTATE CANCER CELLS ACTIVATES EPITHELIAL CELL DIFFERENTIATION

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101304 DOWN-REGULATION OF ERG IN PROSTATE CANCER CELLS ACTIVATES EPITHELIAL CELL DIFFERENTIATION Shyh-Han Tan, Nichelle Shah, Ahmed Mohamed, Taduru Sreenath, Gyorgy Petrovics, Albert Dobi, David G. McLeod, and Shiv Srivastava Shyh-Han TanShyh-Han Tan More articles by this author , Nichelle ShahNichelle Shah More articles by this author , Ahmed MohamedAhmed Mohamed More articles by this author , Taduru SreenathTaduru Sreenath More articles by this author , Gyorgy PetrovicsGyorgy Petrovics More articles by this author , Albert DobiAlbert Dobi More articles by this author , David G. McLeodDavid G. McLeod More articles by this author , and Shiv SrivastavaShiv Srivastava More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.888AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The prostate epithelium consists of luminal and basal cell types. The differentiation from the phenotype of basal cell towards luminal cell can be detected by the expression of specific protein markers: basal epithelial cells express CK-5, CK-14 and p63; luminal epithelial cells express secretory proteins such as PSA, SLC45A3 (prostein) and MSMB (PSP94). Frequent occurrence of the TMPRSS2-ERG gene fusions (>60%) in prostate cancer leads to androgenic induction of the ERG mRNA and protein in tumor cells. We hypothesize that the deregulation of ERG protein expression negatively affects some aspects prostate epithelial differentiation. We aim to understand the function of ERG in the regulation of signaling pathways that affect differentiation of prostate epithelium. METHODS Prostate cancer cells, VCaP which over-express ERG were used in 2-D and 3-D cell culture model systems. We used siRNA and shRNA to deplete the ERG proteins in these cells. The expression of various structural and secretory differentiation markers were examined to by QRT-PCR, Western blots and immuno-fluorescence assays to detect the changes in cell differentiation. The putative promoters that are regulated by ERG were examined by chromatin immuno-precipitation experiments. RESULTS We show that the depletion of ERG by siRNA methods induce changes in cell morphology, concomitant down-regulation of C-MYC and over-expression of cell differentiation markers such as PSA, SLC45A3 and MSMB. Marker of inter-cellular tight junctions, ZO-1 was significantly altered in VCaP cells in response to ERG knock down. Morphology similar to more organized epithelial cellular phenotype was evident in 3-D cultures of VCaP with ERG knockdown. CONCLUSIONS This study suggests that unscheduled expression of ERG oncoprotein in prostate epithelial cells as a result of the fusion of TMPRSS2 promoter to the ERG protein coding sequence may abrogate cell differentiation program favoring cell proliferation. A better understanding of the ERG function in prostate epithelial cell differentiation could lead to the development novel therapeutic strategies for prostate cancer. Rockville, MD© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e504 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shyh-Han Tan More articles by this author Nichelle Shah More articles by this author Ahmed Mohamed More articles by this author Taduru Sreenath More articles by this author Gyorgy Petrovics More articles by this author Albert Dobi More articles by this author David G. McLeod More articles by this author Shiv Srivastava More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...