PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2 Christina Sharkey, Xingbo Long, Ra'ad Al-Faouri, Aria F. Olumi, and Zongwei Wang Christina SharkeyChristina Sharkey More articles by this author , Xingbo LongXingbo Long More articles by this author , Ra'ad Al-FaouriRa'ad Al-Faouri More articles by this author , Aria F. OlumiAria F. Olumi More articles by this author , and Zongwei WangZongwei Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. 5α reductase inhibitors (5ARI) are the only class of benign prostate hyperplasia-related medications that reduce prostate size. However, why the patients respond variably to 5ARI therapies is still largely unknown. We previously demonstrated that 30% of adult human prostatic tissues do not express the SRD5A2 gene and protein via epigenetic modifications. We established a SRD5A2 null (Srd5a2-/-) mouse model and through single cell RNA sequencing, we identified LE2, a sub-cell population of ESR1+ luminal epithelial that is upregulated in Srd5a2-/- mice. Our goal in this study is to characterize the spatial expression of LE2 markers and its functional phenotype when SRD5A2 is absent. METHODS: Homozygous Srd5a2-/- mice and littermate control heterozygous SRD5A2+/- mice were generated and differentially expressed gene profiles of LE2 were obtained from single-cell RNA sequencing (scRNA seq). Spatial expression of LE2 markers was evaluated by RNA fluorescence in-situ hybridization (RNA-FISH). Cell proliferation was detected by Ki67 and BrdU staining. The Cell Death and ER signaling pathways were evaluated with RT2 PCR profiler arrays (84 genes per array) and downstream signaling pathways were analyzed by western blot. Prostate biopsies from the clinical trial of 5ARI for Medical Therapy of Prostatic Symptoms (MTOPS) were used for immunohistochemistry. RESULTS: The prostate weight of Srd5a2-/- mice was significantly decreased compared to Srd5a2+/- littermate control mice (p<0.001). The prostate cell proliferation was suppressed in Srd5a2-/- mice (p=0.05). The cell death signaling akt1, caspase 7, caspase 9, and ER target genes cyp1a1 and vegfa were downregulated (p<0.05). On the other hand, in the anterior lobe of prostate of Srd5a2-/- mice, the cell proliferation was higher than that in control. scRNA seq showed that ESR1 was expressed mainly in the prostate anterior lobe and the number of ESR1+ LE2 cells was significantly increased upon SRD5A2 absence. This was confirmed by RNA-FISH using the probes of LE2 cell markers ESR1 and PVT1. Co-staining of LE2 cell markers ESR1 and PKCa in prostate biopsies of MTOPS further confirmed the existence of an equivalent LE2 cell population in the human prostate with BPH. CONCLUSIONS: Our data demonstrate that LE2, the subpopulation of prostate cells may play an important role in alternative pathways for prostate growth and survival in absence of SRD5A2 and androgen deprivation. Understanding the underlying androgen-independent pathways contributing to prostate growth can help identify novel therapeutic targets for the management of prostatic diseases. Source of Funding: NIH/R01 DK124502 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christina Sharkey More articles by this author Xingbo Long More articles by this author Ra'ad Al-Faouri More articles by this author Aria F. Olumi More articles by this author Zongwei Wang More articles by this author Expand All Advertisement PDF downloadLoading ...