MP37-05 ERP46 MEDIATES PROSTATE CANCER TUMORIGENESIS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research I1 Apr 2015MP37-05 ERP46 MEDIATES PROSTATE CANCER TUMORIGENESIS Wilhelmina Duivenvoorden, Stephanie Federov, Sarah Hopmans, and Jehonathan Pinthus Wilhelmina DuivenvoordenWilhelmina Duivenvoorden More articles by this author , Stephanie FederovStephanie Federov More articles by this author , Sarah HopmansSarah Hopmans More articles by this author , and Jehonathan PinthusJehonathan Pinthus More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.1268AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We have recently demonstrated that endoplasmic reticulum protein ERp46, a member of the protein disulfide isomerase family of oxidoreductases, is overexpressed in metastatic kidney cancer. The expression and function of ERp46 in prostate cancer (PC) has not been studied. We explored the suitability of ERp46 as a potential therapeutic target in PC. METHODS Tissue microarray containing normal prostate epithelium (n=9) and prostate cancer specimens from 57 patients was stained for ERp46. Staining intensity (H-score) was determined (ImageScope). Human prostate adenocarcinoma 22Rv1 cells which are androgen-responsive and produce PSA were used to generate gain- and loss-of-function models by stable ERp46 shRNA knockdown and ERp46 overexpression, respectively. In vitro, the doubling time and PSA production were determined. In vivo, xenografts of each subclone were established in nude mice (n=10/group) to determine the longitudinal tumor growth and serum PSA values. Gene expression profiling of RNA isolated from 22Rv1 xenografts was performed using human whole genome HT-12 V4 BeadChip array (Illumina). RESULTS Human PC samples of Gleason scores (GS) ≥7 showed strong cytoplasmic ERp46 staining which was significantly increased compared to normal prostatic tissue (p=0.02). ERp46 staining in PC samples of GS≤6, however, was not different compared to normal prostate tissue. The stably transfected human prostate carcinoma 22Rv1 cells expressed either 89% knockdown of ERp46 protein expression (shERp46) or a 4-fold increase in ERp46 protein expression (ERp46+) compared to the respective control cells. In vitro, shERp46 cells proliferated slower, whereas ERp46+ cells exhibited accelerated growth compared to corresponding control cells (p<0.05). Similarly, the tumor volume of subcutaneously growing shERp46 cells in nude mice led to significantly slower tumor growth (p<0.0005, ANOVA). Vice versa, tumors from ERp46+ cells were significantly larger than the tumor volume of shControl-cell injected mice (p=0.02, ANOVA). Gene expression analysis confirmed the downregulation and upregulation of ERp46 in the corresponding xenografts and showed several candidate genes, including NAAA, SH3BP4 and ID1 that were reciprocally up-and downregulated. CONCLUSIONS This is the first report to suggest a role for ERp46 as an oncogenic protein and potential therapeutic target in PC given its effects on PC cell growth. Because ERp46 expression is upregulated in significant PC (Gleason score ≥ 7) and not in Gleason score ≤ 6 tumors further investigation of its role as a potential marker and target of clinicaly significant PC is warranted. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e439 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Wilhelmina Duivenvoorden More articles by this author Stephanie Federov More articles by this author Sarah Hopmans More articles by this author Jehonathan Pinthus More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...