{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:12:26Z","timestamp":1790309546824,"version":"4.1.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T00:00:00Z","timestamp":1665360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Decorin (DCN) is a leucine-rich proteoglycan produced by chorionic villus mesenchymal cells anddecidual cells during human pregnancy. Studies from our laboratory demonstrated that decidua-derived DCN restrains multiple trophoblast functions including proliferation, migration, invasion andendovascular differentiation, mediated by DCN-binding to multiple tyrosine kinase receptors; expressed by the trophoblast. Furthermore, DCN was shown to be selectively over-produced by thedecidua in preeclampsia (PE) subjects and elevated in the second trimester maternal plasma in PE, before the appearance of clinical signs, presenting as a predictive biomarker for PE. Micro (mi)RNAs are single-stranded non-coding RNAs (17\u201325 nucleotides) that typically downregulate target genes by repressing translation or facilitating degradation of mRNAs. The human; placenta expresses many miRNAs, some of which are exclusively expressed by the trophoblast. Many; of these miRNAs are dysregulated in PE-associated placentas and some appear in the maternal blood as PE biomarkers. However, little is known about their contribution to the pathogenesis of PE, a multi-factorial disease associated with a hypo-invasive placenta. The objective of the present study was to examine whether exposure of extravillous trophoblast (EVT) to DCN affects expression of specific miRNAs, and to test the role of these miRNAs in altering EVT functions. We identified miR-512-3p, as one of the DCN-induced miRNAs, also upregulated in PE placentas. It was shown to be elevated in ectopic DCN-over-expressing or exogenous DCN-treated first trimester human trophoblast cell line HTR-8\/SVneo. Use of miRNA-mimics and inhibitors revealed that miR-512-3p compromised trophoblast migration, invasion and VEGF-dependent endovascular differentiation. Finally, Protein Phosphatase 3 Regulatory Subunit B, Alpha (PPP3R1), a known target of miR-512-3p, was paradoxically elevated in miR-512-3p-overexpressing trophoblast and PE-associated placentas. Using Enrichr, a tool that consists of both a validated user-submitted gene list and a search engine for transcription factors, we found that PPP3R1 elevation resulted from the miRNA binding to and targeting Upstream Transcription Factor 2 (USF2) which targeted PPP3R1. These findings reveal a novel aspect of pathogenesis of PE and biomarker potentials of this miRNA in PE.<\/jats:p>","DOI":"10.3389\/fcell.2022.1014672","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T13:05:44Z","timestamp":1665407144000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Decorin\u2013induced, preeclampsia-associated microRNA-512-3p restrains extravillous trophoblast functions by targeting USF2\/PPP3R1 axis"],"prefix":"10.3389","volume":"10","author":[{"given":"Chidambra D.","family":"Halari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinki","family":"Nandi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Sidhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Sbirnac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peeyush K.","family":"Lala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"214365","DOI":"10.1155\/2011\/214365","article-title":"Maternal preeclampsia and neonatal outcomes","volume":"2011","author":"Backes","year":"2011","journal-title":"J. Pregnancy"},{"key":"B2","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/nature07242","article-title":"The impact of microRNAs on protein output","volume":"455","author":"Baek","year":"2008","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.placenta.2009.02.009","article-title":"Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"B4","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1530\/REP-10-0294","article-title":"Remodelling at the maternal-fetal interface: Relevance to human pregnancy disorders","volume":"140","author":"Cartwright","year":"2010","journal-title":"Reproduction"},{"key":"B5","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1095\/biolreprod.113.107805","article-title":"Human placental microRNAs and preeclampsia","volume":"88","author":"Chen","year":"2013","journal-title":"Biol. Reprod."},{"key":"B6","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s12964-020-00636-4","article-title":"Calcineurin","volume":"18","author":"Creamer","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"B7","doi-asserted-by":"publisher","first-page":"409","DOI":"10.3389\/fcell.2020.00409","article-title":"MicroRNAs: From mechanism to organism","volume":"8","author":"Dexheimer","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1053\/j.semperi.2009.02.010","article-title":"The global impact of pre-eclampsia and eclampsia","volume":"33","author":"Duley","year":"2009","journal-title":"Semin. Perinatol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"e7515","DOI":"10.1097\/MD.0000000000007515","article-title":"MiR-210 and miR-155 as potential diagnostic markers for pre-eclampsia pregnancies","volume":"96","author":"Gan","year":"2017","journal-title":"Med. Baltim."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1016\/j.biopha.2017.11.053","article-title":"Up-regulation of miR-299 suppressed the invasion and migration of HTR-8\/SVneo trophoblast cells partly via targeting HDAC2 in pre-eclampsia","volume":"97","author":"Gao","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"B11","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1006\/excr.1993.1139","article-title":"Establishment and characterization of first trimester human trophoblast cells with extended lifespan.","volume":"206","author":"Graham","year":"1993","journal-title":"Exp. Cell Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1093\/molehr\/gaaa058","article-title":"Decorin production by the human decidua: Role in decidual cell maturation","volume":"26","author":"Halari","year":"2020","journal-title":"Mol. Hum. Reprod."},{"key":"B13","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/nrg1379","article-title":"MicroRNAs: Small RNAs with a big role in gene regulation","volume":"5","author":"He","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ibmb.2014.10.007","article-title":"Identification of differentially expressed microRNAs in Culex pipiens and their potential roles in pyrethroid resistance","volume":"55","author":"Hong","year":"2014","journal-title":"Insect biochem. Mol. Biol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1695","DOI":"10.1093\/nar\/gkr934","article-title":"Upregulation of Cyclin B1 by miRNA and its implications in cancer","volume":"40","author":"Huang","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"6187","DOI":"10.1210\/en.2008-0780","article-title":"Decorin-mediated inhibition of proliferation and migration of the human trophoblast via different tyrosine kinase receptors","volume":"149","author":"Iacob","year":"2008","journal-title":"Endocrinology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1161\/HYPERTENSIONAHA.111.180232","article-title":"Hydroxysteroid (17-\u03b2) dehydrogenase 1 is dysregulated by miR-210 and miR-518c that are aberrantly expressed in preeclamptic placentas: A novel marker for predicting preeclampsia","volume":"59","author":"Ishibashi","year":"2012","journal-title":"Hypertension"},{"key":"B18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.clinbiochem.2020.02.012","article-title":"Placenta-specific plasma miR518b is a potential biomarker for preeclampsia","volume":"79","author":"Jelena","year":"2020","journal-title":"Clin. Biochem."},{"key":"B19","doi-asserted-by":"publisher","first-page":"10175","DOI":"10.1038\/s41598-019-46599-6","article-title":"Syndecan-4 regulates extravillous trophoblast migration by coordinating protein kinase C activation","volume":"9","author":"Jeyarajah","year":"2019","journal-title":"Sci. Rep."},{"key":"B20","doi-asserted-by":"publisher","first-page":"6117","DOI":"10.1128\/MCB.23.17.6117-6128.2003","article-title":"USF1 and USF2 mediate inhibition of human trophoblast differentiation and CYP19 gene expression by Mash-2 and hypoxia","volume":"23","author":"Jiang","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1095\/biolreprod.102.014977","article-title":"Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia","volume":"69","author":"Kaufmann","year":"2003","journal-title":"Biol. Reprod."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1431","DOI":"10.1210\/me.2010-0426","article-title":"Decorin is a novel VEGFR-2-binding antagonist for the human extravillous trophoblast","volume":"25","author":"Khan","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"190","DOI":"10.3389\/fgene.2013.00190","article-title":"Human placental trophoblast invasion and differentiation: A particular focus on wnt signaling","volume":"4","author":"Kn\u00f6fler","year":"2013","journal-title":"Front. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.jri.2011.02.006","article-title":"Placental-specific microRNA in maternal circulation \u2013 identification of appropriate pregnancy-associated microRNAs with diagnostic potential","volume":"89","author":"Kotlabova","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/jog.12217","article-title":"Placenta-specific miRNA (miR-512-3p) targets PPP3R1 encoding the calcineurin B regulatory subunit in BeWo cells","volume":"40","author":"Kurashina","year":"2014","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1095\/biolreprod.111.097881","article-title":"Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype","volume":"87","author":"Lala","year":"2012","journal-title":"Biol. Reprod."},{"key":"B27","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/s0143-4004(03)00063-8","article-title":"Factors regulating trophoblast migration and invasiveness: Possible derangements contributing to pre-eclampsia and fetal injury","volume":"24","author":"Lala","year":"2003","journal-title":"Placenta"},{"key":"B28","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1080\/19336918.2015.1106669","article-title":"Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: The role of decorin","volume":"10","author":"Lala","year":"2016","journal-title":"Cell adh. Migr."},{"key":"B29","doi-asserted-by":"publisher","first-page":"970265","DOI":"10.1155\/2013\/970265","article-title":"Maternal plasma miRNAs expression in preeclamptic pregnancies","volume":"2013","author":"Li","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"B30","doi-asserted-by":"publisher","first-page":"e2200252119","DOI":"10.1073\/pnas.2200252119","article-title":"Extracellular vesicles secreted by human uterine stromal cells regulate decidualization, angiogenesis, and trophoblast differentiation","volume":"119","author":"Ma","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.3390\/cells10051003","article-title":"Analysis of circulating microRNA signatures and preeclampsia development","volume":"10","author":"Martinez-Fierro","year":"2021","journal-title":"Cells"},{"key":"B32","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1007\/s00404-017-4611-6","article-title":"Circulating levels of specific members of chromosome 19 microRNA cluster are associated with preeclampsia development","volume":"297","author":"Martinez-Fierro","year":"2018","journal-title":"Arch. Gynecol. Obstet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1373\/clinchem.2010.147660","article-title":"Identification of pregnancy-associated microRNAs in maternal plasma","volume":"56","author":"Miura","year":"2010","journal-title":"Clin. Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.jri.2011.01.004","article-title":"MicroRNAs in pregnancy","volume":"88","author":"Morales Prieto","year":"2011","journal-title":"J. Reprod. Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.placenta.2012.05.009","article-title":"MicroRNA expression profiles of trophoblastic cells","volume":"33","author":"Morales-Prieto","year":"2012","journal-title":"Placenta"},{"key":"B36","doi-asserted-by":"publisher","first-page":"686","DOI":"10.3892\/br.2016.779","article-title":"Dysregulated circulating miRNAs in preeclampsia","volume":"5","author":"Munaut","year":"2016","journal-title":"Biomed. Rep."},{"key":"B37","doi-asserted-by":"publisher","first-page":"8977","DOI":"10.1038\/s41598-018-27119-4","article-title":"Human trophoblast stem cell self-renewal and differentiation: Role of decorin","volume":"8","author":"Nandi","year":"2018","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.1073\/pnas.0707594105","article-title":"MicroRNA-373 induces expression of genes with complementary promoter sequences","volume":"105","author":"Place","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1053\/plac.2002.0819","article-title":"Recent Insights into the pathogenesis of pre-eclampsia","volume":"23","author":"Roberts","year":"2002","journal-title":"Placenta"},{"key":"B40","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/nmeth0208-122a","article-title":"When microRNAs activate translation","volume":"5","author":"Rusk","year":"2008","journal-title":"Nat. Methods"},{"key":"B41","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s12978-016-0215-z","article-title":"Health care provider knowledge and routine management of pre-eclampsia in Pakistan","volume":"13","author":"Sheikh","year":"2016","journal-title":"Reprod. Health"},{"key":"B42","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.ajog.2016.03.020","article-title":"Decorin over-expression by decidual cells in preeclampsia: A potential blood biomarker","volume":"215","author":"Siddiqui","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.placenta.2017.11.011","article-title":"Identification of potential early biomarkers of preeclampsia","volume":"61","author":"Timofeeva","year":"2018","journal-title":"Placenta"},{"key":"B44","doi-asserted-by":"publisher","first-page":"4554","DOI":"10.3892\/etm.2017.5067","article-title":"Expression and role of microRNA 18b and hypoxia inducible factor-1\u03b1 in placental tissues of preeclampsia patients","volume":"14","author":"Wang","year":"2017","journal-title":"Exp. Ther. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"E1051","DOI":"10.1210\/jc.2011-3131","article-title":"Preeclampsia up-regulates angiogenesis-associated microRNA (i.e., miR-17, -20a, and -20b) that target ephrin-B2 and EPHB4 in human placenta","volume":"97","author":"Wang","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1080\/15476286.2015.1112487","article-title":"MicroRNAs activate gene transcription epigenetically as an enhancer trigger","volume":"14","author":"Xiao","year":"2017","journal-title":"RNA Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1095\/biolreprod67.2.681","article-title":"Control of proliferation, migration, and invasiveness of human extravillous trophoblast by decorin, a decidual product","volume":"67","author":"Xu","year":"2002","journal-title":"Biol. Reprod."},{"key":"B48","doi-asserted-by":"publisher","first-page":"646326","DOI":"10.3389\/fcell.2021.646326","article-title":"Placenta-derived MicroRNAs in the pathophysiology of human pregnancy","volume":"9","author":"Xu","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1159\/000494744","article-title":"Angiotensin II type I receptor agonistic autoantibody induces podocyte injury via activation of the TRPC6- calcium\/calcineurin pathway in pre-eclampsia.","volume":"43","author":"Yu","year":"2018","journal-title":"Kidney Blood Press. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1016\/j.placenta.2014.11.020","article-title":"Placental miR-106a-363 cluster is dysregulated in preeclamptic placenta","volume":"36","author":"Zhang","year":"2015","journal-title":"Placenta"},{"key":"B51","doi-asserted-by":"publisher","first-page":"E7069","DOI":"10.1073\/pnas.1607849113","article-title":"Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia","volume":"113","author":"Zhang","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B52","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/j.ajog.2008.12.045","article-title":"Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies","volume":"200","author":"Zhu","year":"2009","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"201629","DOI":"10.1155\/2015\/201629","article-title":"Decorin-mediated inhibition of human trophoblast cells proliferation, migration, and invasion and promotion of apoptosis in vitro","volume":"2015","author":"Zou","year":"2015","journal-title":"Biomed. Res. Int."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.1014672\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T13:05:46Z","timestamp":1665407146000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.1014672\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,10]]},"references-count":53,"alternative-id":["10.3389\/fcell.2022.1014672"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.1014672","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,10]]},"article-number":"1014672"}}