Christina Sharkey, Boqing Gu, Xingbo Long, Yao Tang, Nicolas Patsatzis, Steven Li, Aria F Olumi, Zongwei Wang
{"title":"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。","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":"{\"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}","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}
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.
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.
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.