{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T15:37:51Z","timestamp":1790437071290,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["N.82070780, N.81770757, N.82100817"],"award-info":[{"award-number":["N.82070780, N.81770757, N.82100817"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background and objects<\/jats:title><jats:p>Benign prostatic hyperplasia (BPH) is a common disease that impairs the life quality of elderly men. The close relationship of BPH and diabetes has been generally established, however, the exact molecular mechanism remains unclear. Midline-1 (MID1) is an E3 ubiquitin ligase belonging to Tripartite Motif family and its involvement in the initiation and progression of many diseases, such as diabetic kidney disease has been well accepted. This study aims to illuminate the potential impact of high glucose (HG) on prostatic cells and elucidate the molecular role of MID1 in the development of BPH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this work, human prostate specimens and cultured human prostate cell lines (BPH-1 and WPMY-1) were employed. The impact of HG treatment on these two lines was assessed and the expression and localization of MID1, along with its potential downstream target protein phosphatase 2A (PP2A), were determined using multiple experimental methods. MID1-overexpressing cell models were further used to investigate the function of MID1 in regulating inflammation, fibrosis and epithelial-mesenchymal transition (EMT).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Herein we demonstrate diabetic individuals with BPH had lower expression of MID1 and higher expression of the catalytic subunit of PP2A (PP2Ac), larger prostate volume, higher international prostate symptom score (IPSS) and lower Qmax than non-diabetic groups. On a cellular level, HG treatment inhibited the expression of MID1, thus stimulating cellular proliferation and triggering EMT, fibrosis and inflammation of two prostatic cells via enhanced WNT\/\u03b2-catenin signaling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In general, our novel data demonstrate targeting MID1 might be a promising area of medical treatment for patients with both BPH and diabetes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1543295","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T05:51:24Z","timestamp":1742968284000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Midline-1 inhibited high glucose-induced epithelial-mesenchymal transition, fibrosis and inflammation through WNT\/\u03b2-catenin signaling in benign prostatic hyperplasia"],"prefix":"10.3389","volume":"16","author":[{"given":"Xun","family":"Fu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daoquan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"DiSanto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.21037\/tau.2019.10.01","article-title":"Epidemiology and treatment modalities for the management of benign prostatic hyperplasia","volume":"8","author":"Lokeshwar","year":"2019","journal-title":"Transl Androl Urol"},{"key":"B2","article-title":"Benign Prostatic Hyperplasia","volume-title":"StatPearls","author":"Ng","year":"2023"},{"key":"B3","first-page":"S3","article-title":"Benign prostatic hyperplasia: an overview","author":"Roehrborn","year":"2005","journal-title":"Rev Urol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"16031","DOI":"10.1038\/nrdp.2016.31","article-title":"Benign prostatic hyperplasia","volume":"2","author":"Chughtai","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4111\/kju.2012.53.3.139","article-title":"Benign prostatic hyperplasia: from bench to clinic","volume":"53","author":"Yoo","year":"2012","journal-title":"Korean J Urol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2015.301","article-title":"Lower urinary tract symptoms, benign prostatic hyperplasia and metabolic syndrome","volume":"13","author":"Vignozzi","year":"2016","journal-title":"Nat Rev Urol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.26355\/eurrev_201808_15700","article-title":"Correlations of glucose metabolism, insulin resistance and inflammatory factors with symptom score of patients with benign prostatic hyperplasia","volume":"22","author":"Zhou","year":"2018","journal-title":"Eur Rev Med Pharmacol Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"26","DOI":"10.4081\/aiua.2017.1.26","article-title":"Comparison of the clinical parameters of benign prostate hyperplasia in diabetic and non diabetic patients","volume":"89","author":"Ozcan","year":"2017","journal-title":"Arch Ital Urol Androl"},{"key":"B9","doi-asserted-by":"publisher","first-page":"17910","DOI":"10.1038\/s41598-023-44954-2","article-title":"High glucose promotes benign prostatic hyperplasia by downregulating PDK4 expression","volume":"13","author":"Wei","year":"2023","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2020.112145","article-title":"Insulin exacerbated high glucose-induced epithelial-mesenchymal transition in prostatic epithelial cells BPH-1 and prostate cancer cells PC-3 via MEK\/ERK signaling pathway","volume":"394","author":"Yang","year":"2020","journal-title":"Exp Cell Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812666106","article-title":"A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia","volume":"106","author":"Alonso-Magdalena","year":"2009","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2021.1998025","article-title":"Discovery of caffeoylisocitric acid as a Keap1-dependent Nrf2 activator and its effects in mesangial cells under high glucose","volume":"37","author":"Yao","year":"2022","journal-title":"J Enzyme Inhib Med Chem"},{"key":"B13","doi-asserted-by":"publisher","first-page":"F817","DOI":"10.1152\/ajprenal.00602.2015","article-title":"The role of prostate inflammation and fibrosis in lower urinary tract symptoms","volume":"311","author":"Bushman","year":"2016","journal-title":"Am J Physiol Renal Physiol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"F466","DOI":"10.1152\/ajprenal.00116.2021","article-title":"Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction","volume":"321","author":"Pattabiraman","year":"2021","journal-title":"Am J Physiol Renal Physiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.9.2140","article-title":"The tripartite motif family identifies cell compartments","volume":"20","author":"Reymond","year":"2001","journal-title":"EMBO J"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ng762","article-title":"MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation","volume":"29","author":"Trockenbacher","year":"2001","journal-title":"Nat Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s12890-019-0786-x","article-title":"TRAIL signals through the ubiquitin ligase MID1 to promote pulmonary fibrosis","volume":"19","author":"Collison","year":"2019","journal-title":"BMC Pulm Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.709506","article-title":"TRIM18-regulated STAT3 signaling pathway via PTP1B promotes renal epithelial-mesenchymal transition, inflammation, and fibrosis in diabetic kidney disease","volume":"12","author":"Chen","year":"2021","journal-title":"Front Physiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s11884-010-0067-2","article-title":"Benign prostatic hyperplasia and male lower urinary tract symptoms: epidemiology and risk factors","volume":"5","author":"Parsons","year":"2010","journal-title":"Curr Bladder Dysfunct Rep"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-1241.2008.01789.x","article-title":"Modulating an oxidative-inflammatory cascade: potential new treatment strategy for improving glucose metabolism, insulin resistance, and vascular function","volume":"62","author":"Lamb","year":"2008","journal-title":"Int J Clin Pract"},{"key":"B21","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1007\/s11934-019-0917-1","article-title":"Benign prostatic hyperplasia and lower urinary tract symptoms: what is the role and significance of inflammation","volume":"20","author":"Lloyd","year":"2019","journal-title":"Curr Urol Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/bju.12118","article-title":"The role of chronic prostatic inflammation in the pathogenesis and progression of benign prostatic hyperplasia (BPH)","volume":"112","author":"Gandaglia","year":"2013","journal-title":"BJU Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/cells11132052","article-title":"The role of heat shock protein 70 subfamily in the hyperplastic prostate: from molecular mechanisms to therapeutic opportunities","volume":"11","author":"Fu","year":"2022","journal-title":"Cells"},{"key":"B24","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41419-022-04522-4","article-title":"Glucose-regulated protein 78 modulates cell growth, epithelial-mesenchymal transition, and oxidative stress in the hyperplastic prostate","volume":"13","author":"Fu","year":"2022","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1042\/cs20210476","article-title":"NELL2 modulates cell proliferation and apoptosis via ERK pathway in the development of benign prostatic hyperplasia","volume":"135","author":"Liu","year":"2021","journal-title":"Clin Sci (Lond)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/pros.21350","article-title":"TGF-\u03b21-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2\/Slug","volume":"71","author":"Slab\u00e1kov\u00e1","year":"2011","journal-title":"Prostate"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2018.3689","article-title":"Multi\u2212layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT\/\u03b2\u2212catenin signaling activation (Review)","volume":"42","author":"Katoh","year":"2018","journal-title":"Int J Mol Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1080\/0886022x.2022.2044351","article-title":"Relaxin inhibits renal fibrosis and the epithelial-to-mesenchymal transition via the Wnt\/\u03b2-catenin signaling pathway","volume":"44","author":"Feiteng","year":"2022","journal-title":"Ren Fail"},{"key":"B29","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.canlet.2008.10.025","article-title":"Induction of proinflammatory response in prostate cancer epithelial cells by activated macrophages","volume":"276","author":"Wong","year":"2009","journal-title":"Cancer Lett"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20051103","article-title":"Salidroside ameliorates renal interstitial fibrosis by inhibiting the TLR4\/NF-\u03baB and MAPK signaling pathways","volume":"20","author":"Li","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00745","article-title":"Crosstalk between peroxisome proliferator-activated receptor gamma and the canonical WNT\/\u03b2-catenin pathway in chronic inflammation and oxidative stress during carcinogenesis","volume":"9","author":"Vall\u00e9e","year":"2018","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.09.011","article-title":"BMP7-induced-Pten inhibits Akt and prevents renal fibrosis","volume":"1863","author":"Higgins","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2019.08.003","article-title":"Role of AKT and mTOR signaling pathways in the induction of epithelial-mesenchymal transition (EMT) process","volume":"165","author":"Karimi Roshan","year":"2019","journal-title":"Biochimie"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054911","article-title":"Simvastatin improves benign prostatic hyperplasia: role of peroxisome-proliferator-activated receptor-\u03b3 and classic WNT\/\u03b2-catenin pathway","volume":"24","author":"Wang","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3109\/10409238.2016.1143913","article-title":"PP2A as a master regulator of the cell cycle","volume":"51","author":"Wlodarchak","year":"2016","journal-title":"Crit Rev Biochem Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.123192","article-title":"Association between metabolic syndrome and benign prostatic hyperplasia: The underlying molecular connection","volume":"358","author":"Fu","year":"2024","journal-title":"Life Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1543295\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T05:51:36Z","timestamp":1742968296000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1543295\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":36,"alternative-id":["10.3389\/fendo.2025.1543295"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1543295","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]},"article-number":"1543295"}}