https://doi.org/10.4081/ejh.2021.3323
The lncRNA MEG3 promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels
Submitted: 6 September 2021
Accepted: 19 October 2021
Published: 25 November 2021
Accepted: 19 October 2021
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Preeclampsia (PE) is one of the leading causes of maternal morbidity and mortality in pregnant women. This study aimed to investigate the potential impact and regulatory mechanisms of bone morphogenetic protein receptor 2 (BMPR2) on the progression of PE. We obtained placental tissues from pregnant women with PE and normal pregnant women, and the results showed that BMPR2 was expressed at low levels in the tissue from PE women. Genetic knockdown of BMPR2 increased the proliferation and invasion of cultured trophoblast cells, whereas its overexpression reduced these characteristics. Bioinformatics analysis and luciferase reporter gene assays confirmed that BMPR2 is a direct target of miR-21. Overexpression of a miR-21 inhibitor promoted the growth and invasiveness of trophoblast cells, whereas the opposite results were observed for the miR-21 mimic. Furthermore, miR-21 was sponged by the lncRNA MEG3, and shRNA inhibition of MEG3 reduced trophoblast cell growth and invasiveness. miR-21 was upregulated in the tissues from PE women, whereas MEG3 was downregulated, and the two were negatively correlated. Collectively, this study demonstrates that the lncRNA MEG3 acts as a sponge for miR-21, which regulates BMPR2 expression and promotes trophoblast cell proliferation and invasiveness, thereby preventing the development of PE. These findings provide novel insight into a targeted therapy that could be used to treat or prevent the development of PE.
O'Callaghan KM, Kiely M. Systematic review of vitamin D and hypertensive disorders of pregnancy. Nutrients 2018;10:294.
DOI: https://doi.org/10.3390/nu10030294
Zhao X, Wang X. Candesartan targeting of angiotensin II type 1 receptor demonstrates benefits for hypertension in pregnancy via the NFkappaB signaling pathway. Mol Med Rep 2018;18:705-14.
DOI: https://doi.org/10.3892/mmr.2018.9070
Rhoads SJ, Serrano CI, Lynch CE, Ounpraseuth ST, Gauss CH, Payakachat N, et al. Exploring implementation of m-Health monitoring in postpartum women with hypertension. Telemed J E Health 2017;23:833-41.
DOI: https://doi.org/10.1089/tmj.2016.0272
Lim J, Cloete G, Dunsmuir DT, Payne BA, Scheffer C, von Dadelszen P, et al. Usability and feasibility of PIERS on the move: An mHealth app for pre-eclampsia triage. JMIR Mhealth Uhealth 2015;3:e37.
DOI: https://doi.org/10.2196/mhealth.3942
Lai WS, Ding YL. GNG7 silencing promotes the proliferation and differentiation of placental cytotrophoblasts in preeclampsia rats through activation of the mTOR signaling pathway. Int J Mol Med 2019;43:1939-50.
DOI: https://doi.org/10.3892/ijmm.2019.4129
Salem MAA, Ammar IMM. First-trimester uterine artery pulsatility index and maternal serum PAPP-A and PlGF in prediction of preeclampsia in primigravida. J Obstet Gynaecol India 2018;68:192-6.
DOI: https://doi.org/10.1007/s13224-017-1012-5
Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685-700.
DOI: https://doi.org/10.1016/S0092-8674(03)00432-X
Sanchez-Duffhues G, Williams E, Goumans MJ, Heldin CH, Ten Dijke P. Bone morphogenetic protein receptors: Structure, function and targeting by selective small molecule kinase inhibitors. Bone 2020;138:115472.
DOI: https://doi.org/10.1016/j.bone.2020.115472
Andruska A, Spiekerkoetter E. Consequences of BMPR2 deficiency in the pulmonary vasculature and beyond: Contributions to pulmonary arterial hypertension. Int J Mol Sci 2018;19.
DOI: https://doi.org/10.3390/ijms19092499
Luo L, Zheng W, Lian G, Chen H, Li L, Xu C, et al. Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway. Int J Mol Med 2018;41:51-60.
DOI: https://doi.org/10.3892/ijmm.2017.3226
Dannewitz Prosseda S, Ali MK, Spiekerkoetter E. Novel advances in modifying BMPR2 signaling in PAH. Genes (Basel) 2020;12:8.
DOI: https://doi.org/10.3390/genes12010008
Wang J, Zhang C, Zhang Z, Zheng Z, Sun D, Yang Q, et al. A functional variant rs6435156C > T in BMPR2 is associated with increased risk of chronic obstructive pulmonary disease (COPD) in Southern Chinese population. EBioMedicine 2016;5:167-74.
DOI: https://doi.org/10.1016/j.ebiom.2016.02.004
Ye F, Jiang W, Lin W, Wang Y, Chen H, Zou H, et al. A novel BMPR2 mutation in a patient with heritable pulmonary arterial hypertension and suspected hereditary hemorrhagic telangiectasia: A case report. Medicine (Baltimore) 2020;99:e21342.
DOI: https://doi.org/10.1097/MD.0000000000021342
Tanwar VS, Reddy MA, Natarajan R. Emerging role of long non-coding RNAs in diabetic vascular complications. Front Endocrinol (Lausanne) 2021;12:665811.
DOI: https://doi.org/10.3389/fendo.2021.665811
Zhang L, Xu X, Su X. Noncoding RNAs in cancer immunity: functions, regulatory mechanisms, and clinical application. Mol Cancer 2020;19:48.
DOI: https://doi.org/10.1186/s12943-020-01154-0
Forero A, So L, Savan R. Re-evaluating strategies to define the immunoregulatory roles of miRNAs. Trends Immunol 2017;38:558-66.
DOI: https://doi.org/10.1016/j.it.2017.06.001
Song P, Yang F, Jin H, Wang X. The regulation of protein translation and its implications for cancer. Signal Transduct Target Ther 2021;6:68.
DOI: https://doi.org/10.1038/s41392-020-00444-9
Dragomir MP, Kopetz S, Ajani JA, Calin GA. Non-coding RNAs in GI cancers: from cancer hallmarks to clinical utility. Gut 2020;69:748-63.
DOI: https://doi.org/10.1136/gutjnl-2019-318279
Yan Y, Li XQ, Duan JL, Bao CJ, Cui YN, Su ZB, et al. Nanosized functional miRNA liposomes and application in the treatment of TNBC by silencing Slug gene. Int J Nanomedicine 2019;14:3645-67.
DOI: https://doi.org/10.2147/IJN.S207837
Saha S, Chakraborty S, Bhattacharya A, Biswas A, Ain R. MicroRNA regulation of transthyretin in trophoblast differentiation and intra-uterine growth restriction. Sci Rep 2017;7:16548.
DOI: https://doi.org/10.1038/s41598-017-16566-0
Kolkova Z, Holubekova V, Grendar M, Nachajova M, Zubor P, Pribulova T, et al. Association of circulating miRNA expression with preeclampsia, its onset, and severity. Diagnostics (Basel) 2021;11:476.
DOI: https://doi.org/10.3390/diagnostics11030476
Zhang J, Liu X, Gao Y. The long noncoding RNA MEG3 regulates Ras-MAPK pathway through RASA1 in trophoblast and is associated with unexplained recurrent spontaneous abortion. Mol Med 2021;27:70.
DOI: https://doi.org/10.1186/s10020-021-00337-9
Yu Y, Wang L, Gao M, Guan H. Long non-coding RNA TUG1 regulates the migration and invasion of trophoblast-like cells through sponging miR-204-5p. Clin Exp Pharmacol Physiol 2019;46:380-8.
DOI: https://doi.org/10.1111/1440-1681.13058
Wu HY, Wang XH, Liu K, Zhang JL. LncRNA MALAT1 regulates trophoblast cells migration and invasion via miR-206/IGF-1 axis. Cell Cycle 2020;19:39-52.
DOI: https://doi.org/10.1080/15384101.2019.1691787
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife 2015;4:e05005.
DOI: https://doi.org/10.7554/eLife.05005
Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 2014;42:D92-7.
DOI: https://doi.org/10.1093/nar/gkt1248
Jim B, Karumanchi SA. Preeclampsia: Pathogenesis, prevention, and long-term complications. Semin Nephrol 2017;37:386-97.
DOI: https://doi.org/10.1016/j.semnephrol.2017.05.011
Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006;12:642-9.
DOI: https://doi.org/10.1038/nm1429
Wedn AM, El-Bassossy HM, Eid AH, El-Mas MM. Modulation of preeclampsia by the cholinergic anti-inflammatory pathway: Therapeutic perspectives. Biochem Pharmacol 2021;192:114703.
DOI: https://doi.org/10.1016/j.bcp.2021.114703
Pera MF, Andrade J, Houssami S, Reubinoff B, Trounson A, Stanley EG, et al. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci 2004;117:1269-80.
DOI: https://doi.org/10.1242/jcs.00970
Lv Y, Lu C, Ji X, Miao Z, Long W, Ding H, et al. Roles of microRNAs in preeclampsia. J Cell Physiol 2019;234:1052-61.
DOI: https://doi.org/10.1002/jcp.27291
Ma HY, Cu W, Sun YH, Chen X. MiRNA-203a-3p inhibits inflammatory response in preeclampsia through regulating IL24. Eur Rev Med Pharmacol Sci 2020;24:5223-30.
Xueya Z, Yamei L, Sha C, Dan C, Hong S, Xingyu Y, et al. Exosomal encapsulation of miR-125a-5p inhibited trophoblast cell migration and proliferation by regulating the expression of VEGFA in preeclampsia. Biochem Biophys Res Commun 2020;525:646-53.
DOI: https://doi.org/10.1016/j.bbrc.2020.02.137
Hornakova A, Kolkova Z, Holubekova V, Loderer D, Lasabova Z, Biringer K, et al. Diagnostic potential of MicroRNAs as biomarkers in the detection of preeclampsia. Genet Test Mol Biomarkers 2020;24:321-7.
DOI: https://doi.org/10.1089/gtmb.2019.0264
Jairajpuri DS, Malalla ZH, Mahmood N, Almawi WY. Circulating microRNA expression as predictor of preeclampsia and its severity. Gene 2017;627:543-8.
DOI: https://doi.org/10.1016/j.gene.2017.07.010
Bounds KR, Chiasson VL, Pan LJ, Gupta S, Chatterjee P. MicroRNAs: New Players in the Pathobiology of Preeclampsia. Front Cardiovasc Med 2017;4:60.
DOI: https://doi.org/10.3389/fcvm.2017.00060
Dong K, Zhang X, Ma L, Gao N, Tang H, Jian F, et al. Downregulations of circulating miR-31 and miR-21 are associated with preeclampsia. Pregnancy Hypertens 2019;17:59-63.
DOI: https://doi.org/10.1016/j.preghy.2019.05.013
Choi SY, Yun J, Lee OJ, Han HS, Yeo MK, Lee MA, et al. MicroRNA expression profiles in placenta with severe preeclampsia using a PNA-based microarray. Placenta 2013;34:799-804.
DOI: https://doi.org/10.1016/j.placenta.2013.06.006
Zhou F, Sun Y, Gao Q, Wang H. microRNA-21 regulates the proliferation of placental cells via FOXM1 in preeclampsia. Exp Ther Med 2020;20:1871-8.
DOI: https://doi.org/10.3892/etm.2020.8930
Zheng D, Hou Y, Li Y, Bian Y, Khan M, Li F, et al. Long non-coding RNA Gas5 is associated with preeclampsia and regulates biological behaviors of trophoblast via microRNA-21. Front Genet 2020;11:188.
DOI: https://doi.org/10.3389/fgene.2020.00188
Wu JL, Wang YG, Gao GM, Feng L, Guo N, Zhang CX. Overexpression of lncRNA TCL6 promotes preeclampsia progression by regulating PTEN. Eur Rev Med Pharmacol Sci 2019;23:4066-72.
Zhang Y, Zhang M. lncRNA SNHG14 involved in trophoblast cell proliferation, migration, invasion and epithelial-mesenchymal transition by targeting miR-330-5p in preeclampsia. Zygote 2021;29:108-17.
DOI: https://doi.org/10.1017/S0967199420000507
Wang Q, Lu X, Li C, Zhang W, Lv Y, Wang L, et al. Down-regulated long non-coding RNA PVT1 contributes to gestational diabetes mellitus and preeclampsia via regulation of human trophoblast cells. Biomed Pharmacother 2019;120:109501.
DOI: https://doi.org/10.1016/j.biopha.2019.109501
Zhang Y, Zou Y, Wang W, Zuo Q, Jiang Z, Sun M, et al. Down-regulated long non-coding RNA MEG3 and its effect on promoting apoptosis and suppressing migration of trophoblast cells. J Cell Biochem 2015;116:542-50.
DOI: https://doi.org/10.1002/jcb.25004
Wang R, Zou L, Yang X. microRNA-210/ Long non-coding RNA MEG3 axis inhibits trophoblast cell migration and invasion by suppressing EMT process. Placenta 2021;109:64-71.
DOI: https://doi.org/10.1016/j.placenta.2021.04.016
Wang R, Zou L. Downregulation of LncRNA-MEG3 promotes HTR8/SVneo cells apoptosis and attenuates its migration by repressing Notch1 signal in preeclampsia. Reproduction 2020;160:21-9.
DOI: https://doi.org/10.1530/REP-19-0614
Yu L, Kuang LY, He F, Du LL, Li QL, Sun W, et al. The role and molecular mechanism of long nocoding RNA-MEG3 in the pathogenesis of preeclampsia. Reprod Sci 2018;25:1619-28.
DOI: https://doi.org/10.1177/1933719117749753
How to Cite
Liu, H., Cai , X. ., Liu, J. ., Zhang , F. ., He, A. ., & Li, R. (2021). The lncRNA MEG3 promotes trophoblastic cell growth and invasiveness in preeclampsia by acting as a sponge for miR-21, which regulates BMPR2 levels. European Journal of Histochemistry, 65(4). https://doi.org/10.4081/ejh.2021.3323
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