Stromal Steroid 5 α-Reductase Type 2 Promotes Prostate Growth through WNT5A-Lymphoid Enhancer-Binding Factor 1-Insulin-Like Growth Factor 1 Signaling in Benign Prostatic Hyperplasia.

IF 3.6 2区 医学 Q1 PATHOLOGY
Christina Sharkey, Boqing Gu, Xingbo Long, Yao Tang, Nicolas Patsatzis, Steven Li, Aria F Olumi, Zongwei Wang
{"title":"Stromal Steroid 5 α-Reductase Type 2 Promotes Prostate Growth through WNT5A-Lymphoid Enhancer-Binding Factor 1-Insulin-Like Growth Factor 1 Signaling in Benign Prostatic Hyperplasia.","authors":"Christina Sharkey, Boqing Gu, Xingbo Long, Yao Tang, Nicolas Patsatzis, Steven Li, Aria F Olumi, Zongwei Wang","doi":"10.1016/j.ajpath.2025.08.011","DOIUrl":null,"url":null,"abstract":"<p><p>Steroid 5 α-reductase type 2 (SRD5A2) is a key enzyme in androgen metabolism and a pharmacologic target in benign prostatic hyperplasia. Although SRD5A2 is known to mediate stromal-epithelial interactions that influence prostate growth, the relationship between baseline SRD5A2 expression and prostate volume remains unclear. In this study, SRD5A2 expression was analyzed in human prostate tissues from the Medical Therapy of Prostatic Symptoms trial and institutional biorepository cohorts. Quantitative assessments were performed and correlations were evaluated between expression level of SRD5A2, WNT5A, prostate volume, and tissue signaling profiles. SRD5A2 expression was significantly associated with total prostate and transition zone volume. Stromal-specific WNT5A expression showed a strong positive correlation with SRD5A2, whereas neither serum nor tissue dihydrotestosterone levels correlated with SRD5A2 expression. In Srd5a2-null mice, Wnt5a expression in the prostate stroma was dependent on Srd5a2 and showed region-specific regulation. Mechanistically, SRD5A2 overexpression in human prostate stromal cells up-regulated WNT5A and lymphoid enhancer-binding factor 1, activated insulin-like growth factor 1 (IGF1) signaling, increased proliferation, and reduced apoptosis. Conditioned media from these cells enhanced epithelial proliferation through paracrine IGF1 activity. This study provides the first evidence that SRD5A2 promotes prostate growth through a stromal WNT5A-lymphoid enhancer-binding factor 1-IGF1 paracrine signaling axis independent of androgen levels, suggesting a novel therapeutic mechanism relevant for patients with benign prostatic hyperplasia with resistance to conventional 5 α-reductase inhibitor therapy.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2025.08.011","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Steroid 5 α-reductase type 2 (SRD5A2) is a key enzyme in androgen metabolism and a pharmacologic target in benign prostatic hyperplasia. Although SRD5A2 is known to mediate stromal-epithelial interactions that influence prostate growth, the relationship between baseline SRD5A2 expression and prostate volume remains unclear. In this study, SRD5A2 expression was analyzed in human prostate tissues from the Medical Therapy of Prostatic Symptoms trial and institutional biorepository cohorts. Quantitative assessments were performed and correlations were evaluated between expression level of SRD5A2, WNT5A, prostate volume, and tissue signaling profiles. SRD5A2 expression was significantly associated with total prostate and transition zone volume. Stromal-specific WNT5A expression showed a strong positive correlation with SRD5A2, whereas neither serum nor tissue dihydrotestosterone levels correlated with SRD5A2 expression. In Srd5a2-null mice, Wnt5a expression in the prostate stroma was dependent on Srd5a2 and showed region-specific regulation. Mechanistically, SRD5A2 overexpression in human prostate stromal cells up-regulated WNT5A and lymphoid enhancer-binding factor 1, activated insulin-like growth factor 1 (IGF1) signaling, increased proliferation, and reduced apoptosis. Conditioned media from these cells enhanced epithelial proliferation through paracrine IGF1 activity. This study provides the first evidence that SRD5A2 promotes prostate growth through a stromal WNT5A-lymphoid enhancer-binding factor 1-IGF1 paracrine signaling axis independent of androgen levels, suggesting a novel therapeutic mechanism relevant for patients with benign prostatic hyperplasia with resistance to conventional 5 α-reductase inhibitor therapy.

在良性前列腺增生中,基质SRD5A2通过WNT5A-LEF1-IGF1信号通路促进前列腺生长。
类固醇5 α -还原酶2型(SRD5A2)是雄激素代谢的关键酶,也是良性前列腺增生(BPH)的一个药理靶点。虽然已知SRD5A2介导影响前列腺生长的基质-上皮相互作用,但SRD5A2基线表达与前列腺体积之间的关系尚不清楚。在这项研究中,我们分析了来自前列腺症状医学治疗(MTOPS)试验和机构生物库队列的SRD5A2在人前列腺组织中的表达。进行定量评估,并评估SRD5A2、WNT5A表达水平、前列腺体积和组织信号谱之间的相关性。SRD5A2的表达与前列腺总体积和转移区体积显著相关。基质特异性WNT5A表达与SRD5A2呈强正相关,而血清和组织双氢睾酮水平与SRD5A2表达无关。在Srd5a2缺失的小鼠中,Wnt5a在前列腺基质中的表达依赖于Srd5a2,并表现出区域特异性调控。在机制上,SRD5A2在人前列腺基质细胞中过表达上调WNT5A和淋巴增强因子结合因子1 (LEF1),激活胰岛素样生长因子1 (IGF1)信号,增加增殖,减少凋亡。来自这些细胞的条件培养基通过旁分泌IGF1活性增强上皮细胞增殖。本研究首次证明SRD5A2通过不依赖于雄激素水平的基质WNT5A-LEF1-IGF1旁分泌信号轴促进前列腺生长,提示对常规5 α -还原酶抑制剂治疗耐药的BPH患者存在一种新的治疗机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信