{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:43:55Z","timestamp":1774658635787,"version":"3.50.1"},"reference-count":36,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T00:00:00Z","timestamp":1653350400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD069043"],"award-info":[{"award-number":["R01HD069043"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: miR-451a can function as a tumor suppresser and has been shown to be elevated in both endometriotic lesion tissue and serum from women with endometriosis. To further explore the role of miR-451a in the pathophysiology of endometriosis, specifically, further evaluating its association with the tumor suppressor, phosphatase and tensin homolog (PTEN), we examined their expression in individual endometriotic lesion tissue to gain insight into their relationship and further explore if miR-451a regulates PTEN expression. Methods: A total of 55 red, peritoneal endometriotic lesions and matched eutopic endometrial specimens were obtained from 46 patients with endometriosis. miR-451a, miR-25-3p and PTEN mRNA levels were assessed by qRT-PCR and reported for each matched eutopic and ectopic sample. To evaluate miR-451a and miR-25-3p expression of miR-25-3p and PTEN, respectively, 12Z cells (endometriotic epithelial cell line) were transfected and miR-25-3p expression was assessed by qRT-PCR, while PTEN protein expression was assessed by Western blotting. Results: PTEN and miR-25-3p expression exhibited an inverse relationship, as did miR-25-3p and miR-451a in individual lesions. Over-expression of miR-451a in 12Z cells resulted in down-regulation of miR-25-3p, while up-regulation of miR-25-3p resulted in down-regulation of PTEN protein expression. Conclusions: By assessing individual endometriotic lesion expression, we discovered an inverse relationship between miR-451a, miR-25-3p and PTEN, while in vitro cell transfection studies suggest that miR-451a may regulate PTEN expression via modulating miR-25-3p.<\/jats:p>","DOI":"10.3390\/ijms23115862","type":"journal-article","created":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:04:06Z","timestamp":1653429846000},"page":"5862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Relationship and Expression of miR-451a, miR-25-3p and PTEN in Early Peritoneal Endometriotic Lesions and Their Modulation In Vitro"],"prefix":"10.3390","volume":"23","author":[{"given":"Warren B.","family":"Nothnick","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA"},{"name":"Institute for Reproduction and Perinatal Research, Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riley","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paige","family":"Minchella","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tommaso","family":"Falcone","sequence":"additional","affiliation":[{"name":"Cleveland Clinic, London E1 4DG, UK"},{"name":"Cleveland Clinic, Lerner College of Medicine, Cleveland, OH 44101, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"Findley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.fertnstert.2012.06.029","article-title":"Pathogenesis and pathophysiology of endometriosis","volume":"98","author":"Burney","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(04)17403-5","article-title":"Endometriosis","volume":"364","author":"Giudice","year":"2004","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0002-9378(40)91238-8","article-title":"The development of the implantation theory for the origin of peritoneal endometriosis","volume":"40","author":"Sampson","year":"1940","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_4","first-page":"151","article-title":"Retrograde menstruation in healthy women and in patients with endometriosis","volume":"64","author":"Halme","year":"1984","journal-title":"Obstet. Gynecol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Smolarz, B., Szy\u0142\u0142o, K., and Romanowicz, H. (2021). Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (review of the literature). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910554"},{"key":"ref_6","first-page":"1135","article-title":"MicroRNAs in endometriosis: Biological function and emerging biomarker candidates","volume":"100","author":"Bjorkman","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/humupd\/dmy014","article-title":"Non-coding RNAs in endometriosis: A narrative review","volume":"24","author":"Panir","year":"2018","journal-title":"Hum. Reprod. Update"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1055\/s-0037-1599089","article-title":"MicroRNAs and Endometriosis: Distinguishing drivers from passengers in disease pathogenesis","volume":"35","author":"Nothnick","year":"2017","journal-title":"Semin. Reprod. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1093\/humrep\/dev005","article-title":"The expression of microRNA-451 in human endometriotic lesions is inversely related to that of macrophage migration inhibitory factor (MIF) and regulates MIF expression and modulation of epithelial cell survival","volume":"30","author":"Graham","year":"2015","journal-title":"Hum. Reprod."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8823","DOI":"10.1038\/s41598-019-45243-7","article-title":"Human endometriotic lesion expression of the miR-144-3p\/miR-451a cluster, its correlation with markers of cell survival and origin of lesion content","volume":"9","author":"Nothnick","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1177\/1933719116681519","article-title":"Serum miR-451a levels are significantly elevated in women with endometriosis and recapitulated in, baboons (Papio anubis) with experimentally-induced disease","volume":"24","author":"Nothnick","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nothnick, W.B., Graham, A., Holbert, J., and Weiss, M.J. (2014). miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0100336"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1126\/science.275.5308.1943","article-title":"PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer","volume":"275","author":"Li","year":"1997","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/ng0497-356","article-title":"Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers","volume":"15","author":"Steck","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_15","first-page":"1","article-title":"Microarray analysis of microRNA deregulation and angiogenesis-related proteins in endometriosis","volume":"15","author":"Yang","year":"2016","journal-title":"Genet. Mol. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"117190","DOI":"10.1016\/j.lfs.2019.117190","article-title":"miR-92a promotes progesterone resistance in endometriosis through PTEN\/AKT pathway","volume":"242","author":"Li","year":"2020","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1080\/09513590.2019.1680627","article-title":"PI3K\/AKT pathway is altered in the endometriosis patient\u2019s endometrium and presents differences according to severity stage","volume":"36","author":"Madanes","year":"2020","journal-title":"Gynecol. Endocrinol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaav1741","DOI":"10.1126\/science.aav1741","article-title":"The biochemical basis of microRNA targeting efficacy","volume":"366","author":"McGeary","year":"2019","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D360","DOI":"10.1093\/nar\/gkx1144","article-title":"mirDIP4.1\u2013integrative database of human microRNA target predictions","volume":"46","author":"Tokar","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13059-019-1629-z","article-title":"Prediction of functional miRNA targets by integrative modeling of microRNA binding and target expression data","volume":"20","author":"Liu","year":"2019","journal-title":"Genome Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109111","DOI":"10.1016\/j.biopha.2019.109111","article-title":"MiR-25-3p promotes malignant phenotypes of retinoblastoma by regulating PTEN\/Akt pathway","volume":"118","author":"Wan","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"BSR20201901","DOI":"10.1042\/BSR20201901","article-title":"MiR-25-3p targets PTEN to regulate the migration, invasion, and apoptosis of esophageal cancer cells via the PI3K\/AKT pathway","volume":"40","author":"Zhang","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3892\/ijmm.2020.4841","article-title":"Downregulation of microRNA-25-3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN\/PI3K\/AKT signaling pathway","volume":"47","author":"Zi","year":"2021","journal-title":"Int. J. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"369549","DOI":"10.1155\/2010\/369549","article-title":"Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis","volume":"2010","author":"Filigheddu","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3892\/ijmm.2013.1536","article-title":"Downregulation of miR-183 inhibits apoptosis and enhances the invasive potential of endometrial stromal cells in endometriosis","volume":"33","author":"Shi","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"300060520918437","DOI":"10.1177\/0300060520918437","article-title":"The miR-25-3p\/Sp1 pathway is dysregulated in ovarian endometriosis","volume":"48","author":"Shen","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1210\/me.2008-0387","article-title":"MicroRNA-regulated pathways associated with endometriosis","volume":"23","author":"Perry","year":"2009","journal-title":"Mol. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.trecan.2018.05.002","article-title":"MicroRNAs regulating microRNAs in cancer","volume":"4","author":"Hill","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"dmm047662","DOI":"10.1242\/dmm.047662","article-title":"miRNA interplay: Mechanisms and consequences in cancer","volume":"14","author":"Hill","year":"2021","journal-title":"Dis. Model Mech."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/leu.2009.246","article-title":"Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation","volume":"24","author":"Forrest","year":"2010","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/cr.2011.137","article-title":"Mouse miRNA-709 directly regulates miRNA-15a\/16-1 biogenesis at the posttranscriptional level in the nucleus: Evidence for a microRNA hierarchy system","volume":"22","author":"Tang","year":"2012","journal-title":"Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3442","DOI":"10.1172\/JCI45390","article-title":"miR-107 promotes tumor progression by targeting the let-7 microRNA in mice and humans","volume":"121","author":"Chen","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.fertnstert.2016.04.013","article-title":"Serum microRNAs as diagnostic markers of endometriosis: A comprehensive array-based analysis","volume":"106","author":"Cosar","year":"2016","journal-title":"Fertil. Steril."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"557.e1","DOI":"10.1016\/j.ajog.2020.02.050","article-title":"Accurate diagnosis of endometriosis using serum microRNAs","volume":"223","author":"Moustafa","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"American Society for Reproductive Medicine (1997). Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil. Steril., 67, 817\u2013821.","DOI":"10.1016\/S0015-0282(97)81391-X"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1093\/molehr\/gaz065","article-title":"60S acidic ribosomal protein P1 (RPLP1) is elevated in human endometriotic tissue and in a murine model of endometriosis and is essential for endometriotic epithelial cell survival in vitro","volume":"26","author":"Alali","year":"2020","journal-title":"Mol. Hum. Reprod."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5862\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:17:25Z","timestamp":1760138245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/11\/5862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,24]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23115862"],"URL":"https:\/\/doi.org\/10.3390\/ijms23115862","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,24]]}}}