PD05-10 LOSS OF MIR-21 DELAYS MYC-DRIVEN PROSTATE CANCER PROGRESSION IN THE HI-MYC TRANSGENIC MOUSE MODEL (2019)

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (PD05)1 Apr 2019PD05-10 LOSS OF MIR-21 DELAYS MYC-DRIVEN PROSTATE CANCER PROGRESSION IN THE HI-MYC TRANSGENIC MOUSE MODEL Kenji Zennami*, Fatima Rafiqi, Ross Liao, Kim Sealover, Brian Simons, Makoto Sumitomo, Ryoichi Shiroki, and Shawn Lupold Kenji Zennami*Kenji Zennami* More articles by this author , Fatima RafiqiFatima Rafiqi More articles by this author , Ross LiaoRoss Liao More articles by this author , Kim SealoverKim Sealover More articles by this author , Brian SimonsBrian Simons More articles by this author , Makoto SumitomoMakoto Sumitomo More articles by this author , Ryoichi ShirokiRyoichi Shiroki More articles by this author , and Shawn LupoldShawn Lupold More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555070.63543.0bAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: MicroRNA 21 (miR-21) is overexpressed in virtually all types of cancers including prostate cancer (PCa). We have previously reported that the androgen receptor (AR) induces miR-21 expression, and that elevated miR-21 is sufficient to drive PCa growth and castration resistance. However, the role of miR-21 in PCa initiation and progression has not been fully elucidated. To determine if the absence of miR-21 inhibits or delays prostate cancer incidence or progression, we crossed miR-21 KO mice with Hi-Myc mice. In this study, we identify that loss of miR-21 delays Myc-driven prostate cancer progression in the Hi-Myc transgenic mouse model. METHODS: miR-21 KO mice were backcrossed to FVB mice to generation F10. Resulting miR-21 WT or KO FVB progeny were crossed with Hi-Myc mice to generate Hi-Myc/miR-21 WT or KO mice. Prostates were harvested at 4 weeks (n=10), 3 months (n=10), 5 months (n=58), 6 months (n=25), 8 months (n=20) of age and prostate weight, histology, miR-21 expression levels and protein expression levels were quantified. Proliferation and apoptosis were examined by immunohistochemistry using Ki-67 and cleaved caspase-3. RESULTS: Cancerous prostates of Hi-Myc mice showed high miR-21 expression at 5m and 8m, when compared to FVB controls (Fig. 1A). Hi-Myc/miR-21 KO mice demonstrated a marked reduction in adenocarcinoma when compared to Hi-Myc/miR-21 WT mice at 5m (Fig. 1B). This is apparent in the reduced weight of effected prostate lobes of Hi-Myc/miR-21 KO versus WT mice at 8m (Fig. 1C). Protein levels of established miR-21 target genes, PDCD4 and PTEN, were up-regulated in the prostates of Hi-Myc/miR-21 KO mice (Fig. 1D). Also, IHC showed lower Ki-67 and higher cleaved caspase-3 positive cells in miR-21 KO than WT (Fig. 1E, F). However, miR-21 KO did not affect prostatic intraepithelial neoplasia (PIN) development. CONCLUSIONS: Our results demonstrate that miR-21 delays Myc-driven prostate cancer progression through reduced proliferation and enhanced apoptosis, and that endogenous miR-21 suppresses prostatic PDCD4 and PTEN protein expression levels. Therefore, targeting of miR-21 or its downstream target genes may be useful for cancer prevention or cancer therapy. Source of Funding: NIH (R01-CA143299) and the Patrick C. Walsh Prostate Cancer Research Fund. Toyoake, Japan; Baltimore, MD; Toyoake, Japan; Baltimore, MD© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e83-e84 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kenji Zennami* More articles by this author Fatima Rafiqi More articles by this author Ross Liao More articles by this author Kim Sealover More articles by this author Brian Simons More articles by this author Makoto Sumitomo More articles by this author Ryoichi Shiroki More articles by this author Shawn Lupold More articles by this author Expand All Advertisement PDF downloadLoading ...