Functional Roles of lncRNAs in Recurrent Pregnancy Loss: A Review Study

Document Type : Review Article


1 Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Obstetrics and Gynecology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

3 Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

4 Department of Animal Physiology, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran

5 Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran

6 Department of Obstetrics and Gynecology, Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

7 Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran


Recurrent pregnancy loss (RPL) or recurrent miscarriage is the failure of pregnancy before 20-24 weeks that influences
around 2-5% of couples. Several genetic, immunological, environmental and physical factors may influence
RPL. Although various traditional methods have been used to treat post-implantation failures, identifying the mechanisms
underlying RPL may improve an effective treatment. Recent evidence suggested that gene expression alterations
presented essential roles in the occurrence of RPL. It has been found that long non-coding RNAs (lncRNAs) play
functional roles in pregnancy pathologies, such as recurrent miscarriage. lncRNAs can function as dynamic scaffolds,
modulate chromatin function, guide and bind to microRNAs (miRNAs) or transcription factors. lncRNAs, by targeting
various miRNAs and mRNAs, play essential roles in the progression or suppression of RPL. Therefore, targeting
lncRNAs and their downstream targets might be a suitable strategy for diagnosis and treatment of RPL. In this review,
we summarized emerging roles of several lncRNAs in stimulation or suppression of RPL.


Main Subjects

  1. Azin SA, Golbabaei F, Warmelink JC, Eghtedari S, Haghani S, Ranjbar F. Association of depression with sexual function in women with history of recurrent pregnancy loss: descriptive-correlational study in Tehran, Iran. Fertil Res Pract. 2020; 6(1): 1-9.
  2. El Hachem H, Crepaux V, May-Panloup P, Descamps P, Legendre G, Bouet PE. Recurrent pregnancy loss: current perspectives. Int J Womens Health. 2017; 9: 331-345.
  3. Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Re­current pregnancy loss. Nat Rev Dis Primers. 2020; 6(1): 98.
  4. Habets DHJ, Pelzner K, Wieten L, Spaanderman MEA, Villamor E, Al-Nasiry S. Intravenous immunoglobulins improve live birth rate among women with underlying immune conditions and recurrent pregnancy loss: a systematic review and meta-analysis. Allergy Asthma Clin Immunol. 2022; 18(1): 23.
  5. Otani-Matsuura A, Sugiura-Ogasawara M, Ebara T, Matsuki T, Tamada H, Yamada Y, et al. Depression symptoms during preg­nancy and postpartum in patients with recurrent pregnancy loss and infertility: the Japan environment and children's study. J Re­prod Immunol. 2022; 152: 103659.
  6. Mekinian A, Cohen J, Alijotas-Reig J, Carbillon L, Nicaise-Roland P, Kayem G, et al. Unexplained recurrent miscarriage and recurrent implantation failure: is there a place for immunomodulation? Am J Reprod Immunol. 2016; 76(1): 8-28.
  7. Gaboon NE, Mohamed AR, Elsayed SM, Zaki OK, Elsayed MA. Structural chromosomal abnormalities in couples with recurrent abortion in Egypt. Turk J Med Sci. 2015; 45(1): 208-213.
  8. Houmaid H, El Bekkay C, Nassereddine S, Talbi H, Amehdare L, Hilali A. Chromosomal abnormalities in 238 couples with recurrent miscarriages in Morocco. Open J Genet. 2018; 8(02): 15-22.
  9. Abdoli A, Dalimi A, Soltanghoraee H, Ghaffarifar F. Molecular de­tection and genotypic characterization of toxoplasma gondii in paraffin-embedded fetoplacental tissues of women with recurrent spontaneous abortion. Int J Fertil Steril. 2017; 10(4): 327-336.
  10. Amrane S, McConnell R. Endocrine causes of recurrent pregnancy loss. Semin Perinatol. 2019; 43(2): 80-83.
  11. Devall AJ, Coomarasamy A. Sporadic pregnancy loss and recur­rent miscarriage. Best Pract Res Clin Obstet Gynaecol. 2020; 69: 30-39.
  12. Kuroda K. Impaired endometrial function and unexplained recur­rent pregnancy loss. Hypertens Res Pregnancy. 2019: 7(1): 16-21.
  13. Quenby S, Gallos ID, Dhillon-Smith RK, Podesek M, Stephenson MD, Fisher J, et al. Miscarriage matters: the epidemiological, phys­ical, psychological, and economic costs of early pregnancy loss. Lancet. 2021; 397(10285): 1658-1667.
  14. Alves C, Rapp A. Spontaneous abortion. Available from: https:// (26 Jul 2022).
  15. Kolte A, Olsen L, Mikkelsen E, Christiansen O, Nielsen H. Depres­sion and emotional stress is highly prevalent among women with recurrent pregnancy loss. Hum Reprod. 2015; 30(4): 777-782.
  16. Arias-Sosa LA, Acosta ID, Lucena-Quevedo E, Moreno-Ortiz H, Esteban-Pérez C, Forero-Castro M. Genetic and epigenetic varia­tions associated with idiopathic recurrent pregnancy loss. J Assist Reprod Genet. 2018; 35(3): 355-366.
  17. Xu WW, Jin J, Wu XY, Ren QL, Farzaneh M. MALAT1-related sign­aling pathways in colorectal cancer. Cancer Cell Int. 2022; 22(1): 126.
  18. Huang Z, Du G, Huang X, Han L, Han X, Xu B, et al. The enhancer RNA lnc-SLC4A1-1 epigenetically regulates unexplained recurrent pregnancy loss (URPL) by activating CXCL8 and NF-kB pathway. EBioMedicine. 2018; 38: 162-170.
  19. Chen X, Guo DY, Yin TL, Yang J. Non-coding RNAs regulate pla­cental trophoblast function and participate in recurrent abortion. Front Pharmacol. 2021; 12: 646521.
  20. Wang L, Tang H, Xiong Y, Tang L. Differential expression profile of long noncoding RNAs in human chorionic villi of early recurrent miscarriage. Clin Chim Acta. 2017; 464: 17-23.
  21. Yang D, Ding J, Wang Y, Yuan M, Xian S, Zhang L, et al. YY1-PVT1 affects trophoblast invasion and adhesion by regulating mTOR pathway-mediated autophagy. J Cell Physiol. 2020; 235(10): 6637- 6646.
  22. Farzaneh M, Najafi S, Dari MAG, Sheykhi-Sabzehpoush M, Dayer D, Cheraghzadeh M, et al. Functional roles of long noncoding RNA MALAT1 in gynecologic cancers. Clin Transl Oncol. 2023; 25(1): 48-65.
  23. Tong YS, Wang XW, Zhou XL, Liu ZH, Yang TX, Shi WH, et al. Identification of the long non-coding RNA POU3F3 in plasma as a novel biomarker for diagnosis of esophageal squamous cell carci­noma. Mol Cancer. 2015; 14: 3.
  24. Patty BJ, Hainer SJ. Non-coding RNAs and nucleosome remod­eling complexes: an intricate regulatory relationship. Biology (Ba­sel). 2020; 9(8): 213.
  25. Anbiyaiee A, Ramazii M, Bajestani SS, Meybodi SM, Keivan M, Khoshnam SE, et al. The function of LncRNA-ATB in cancer. Clin Transl Oncol. 2022 (ahead of print).
  26. Farzaneh M, Ghasemian M, Ghaedrahmati F, Poodineh J, Najafi S, Masoodi T, et al. Functional roles of lncRNA-TUG1 in hepatocel­lular carcinoma. Life Sci. 2022; 308: 120974.
  27. Uesaka M, Nishimura O, Go Y, Nakashima K, Agata K, Imamura T. Bidirectional promoters are the major source of gene activation-associated non-coding RNAs in mammals. BMC Genomics. 2014; 15: 35.
  28. Zhou M, Guo X, Wang M, Qin R. The patterns of antisense long non-coding RNAs regulating corresponding sense genes in human cancers. J Cancer. 2021; 12(5): 1499-1506.
  29. Ousati Ashtiani Z, Abbasi S, Pourmand G, Ghafouri-Fard S. Over­expression of long intergenic noncoding RNAs in bladder cancer: a new insight to cancer diagnosis. Pathol Res Pract. 2022; 235: 153961.
  30. Chen LL. Linking long noncoding RNA localization and function. Trends Biochem Sci. 2016; 41(9): 761-772.
  31. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021; 22(2): 96-118.
  32. Ma L, Bajic VB, Zhang Z. On the classification of long non-coding RNAs. RNA Biol. 2013; 10(6): 925-933.
  33. Wu R, Su Y, Wu H, Dai Y, Zhao M, Lu Q. Characters, functions and clinical perspectives of long non-coding RNAs. Mol Genet Genom­ics. 2016; 291(3): 1013-1033.
  34. Che D, Fang Z, Mai H, Xu Y, Fu L, Zhou H, et al. The lncRNA ANRIL gene rs2151280 GG genotype is associated with increased susceptibility to recurrent miscarriage in a southern chinese popu­lation. J Inflamm Res. 2021; 14: 2865-2872.
  35.  Zhang Y, Wang S. The possible role of long non-coding RNAs in recurrent miscarriage. Mol Biol Rep. 2022; 49(10): 9687-9697.
  36. Chen X, Guo DY, Yin TL, Yang J. Non-coding RNAs regulate pla­cental trophoblast function and participate in recurrent abortion. Front Pharmacol. 2021; 12: 646521.
  37. Liu LP, Gong YB. LncRNA-TCL6 promotes early abortion and in­hibits placenta implantation via the EGFR pathway. Eur Rev Med Pharmacol Sci. 2018; 22(21): 7105-7112.
  38. Xiang H, Yan H, Sun B, Feng F, Chen P. Decreased expression of long non-coding RNA SNHG7 cause recurrent spontaneous abor­tion through suppression proliferation and invasion of trophoblast cells via miR-34a. Am J Transl Res. 2019; 11(1): 463-472.
  39.  Bai RX, Tang ZY. Long non-coding RNA H19 regulates Bcl-2, Bax and phospholipid hydroperoxide glutathione peroxidase expres­sion in spontaneous abortion. Exp Ther Med. 2021; 21(1): 41.
  40. He D, Zeng H, Chen J, Xiao L, Zhao Y, Liu N. H19 regulates tropho­blastic spheroid adhesion by competitively binding to let-7. Repro­duction. 2019; 157(5): 423-430.
  41.  Gao WL, Liu M, Yang Y, Yang H, Liao Q, Bai Y, et al. The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1). RNA Biol. 2012; 9(7): 1002-1010.
  42.  Liao M, Liao W, Xu N, Li B, Liu F, Zhang S, et al. LncRNA EP­B41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2. EBioMedicine. 2019; 41: 200- 213.
  43. Huang W, Zhou H, Pi L, Xu Y, Fu L, Yang Y, et al. Association be­tween the rs2288947 polymorphism of the lncRNA TINCR gene and the risk of recurrent miscarriage in a Southern Chinese popula­tion. J Clin Lab Anal. 2019; 33(6): e22919.
  44.  Wang Y, Liu HZ, Liu Y, Wang HJ, Pang WW, Zhang JJ. Downregu­lated MALAT1 relates to recurrent pregnancy loss via sponging miR­NAs. Kaohsiung J Med Sci. 2018; 34(9): 503-510.
  45.  Che D, Yang Y, Xu Y, Fang Z, Pi L, Fu L, et al. The lncRNA MALAT1 rs619586 G variant confers decreased susceptibility to recurrent miscarriage. Front Physiol. 2019; 10: 385.
  46.  Fang Z, Che D, Qing S, Li Q, Men H, Yuan L, et al. The lncRNA SOX2OT rs9839776 C>T Polymorphism indicates recurrent mis­carriage susceptibility in a southern chinese population. Mediators Inflamm. 2019; 2019: 9684703.
  47.  Li H, Hou Y, Zhang S, Zhou Y, Wang D, Tao S, et al. CD49a regu­lates the function of human decidual natural killer cells. Am J Re­prod Immunol. 2019; 81(4): e13101.
  48.  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(1): 70.
  49.  Yu N, Chen X, Du M, Li H, Wang Y, Jiang F, et al. Long non-coding RNA ZEB2-AS1 augments activity of trophoblast cells and pre­vents the development of recurrent spontaneous abortion in mice through EZH2-Mediated CST3 inhibition. Reprod Sci. 2022; 29(3): 963-974.
  50.  Fang Z, Che D, Qing S, Li Q, Men H, Yuan L, et al. The lncRNA SOX2OT rs9839776 C>T polymorphism indicates recurrent mis­carriage susceptibility in a southern Chinese population. Mediators Inflamm. 2019; 2019: 9684703.
  51.  Teng L, Liu P, Song X, Wang H, Sun J, Yin Z. Long non-coding RNA nuclear-enriched abundant transcript 1 (NEAT1) represses proliferation of trophoblast cells in rats with preeclampsia via the MicroRNA-373/FLT1 Axis. Med Sci Monit. 2020; 26: e927305.
  52.  Che D, Huang W, Fang Z, Li L, Wu H, Pi L, et al. The lncRNA CCAT2 rs6983267 G allele is associated with decreased suscepti­bility to recurrent miscarriage. J Cell Physiol. 2019; 234(11): 20577- 20583.
  53.  Tian FJ, He XY, Wang J, Li X, Ma XL, Wu F, et al. Elevated tris­tetraprolin impairs trophoblast invasion in women with recurrent miscarriage by destabilization of HOTAIR. Mol Ther Nucleic Acids. 2018; 12: 600-609.
  54.  Xie J, Liang T, Zhao J, Xu Z, Tian P, Wang R, et al. Lnc-HZ08 regulates BPDE-induced trophoblast cell dysfunctions by promot­ing PI3K ubiquitin degradation and is associated with miscarriage. Cell Biol Toxicol. 2022; 38(2): 291-310.
  55.  Xu Z, Tian P, Guo J, Mi C, Liang T, Xie J, et al. Lnc-HZ01 with m6A RNA methylation inhibits human trophoblast cell proliferation and induces miscarriage by up-regulating BPDE-activated lnc- HZ01/MXD1 positive feedback loop. Sci Total Environ. 2021; 776: 145950.
  56.  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(10): 4066-4072.
  57.  Wang H, Shen G, Liu M, Mao L, Mao H. Expression and clinical sig­nificance of lncRNA TCL6 in serum of patients with preeclampsia. Exp Ther Med. 2022; 23(1): 41.
  58.  Chen X, Guo DY, Yin TL, Yang J. Non-coding RNAs regulate pla­cental trophoblast function and participate in recurrent abortion. Front Pharmacol. 2021; 12: 646521.
  59. Bian Z, Ji W, Xu B, Huang W, Jiao J, Shao J, et al. The role of long noncoding RNA SNHG7 in human cancers (Review). Mol Clin On­col. 2020; 13(5): 45.
  60. Pei LJ, Sun PJ, Ma K, Guo YY, Wang LY, Liu FD. LncRNA-SNHG7 interferes with miR-34a to de-sensitize gastric cancer cells to cispl­atin. Cancer Biomark. 2021; 30(1): 127-137.
  61. Olgun G, Sahin O, Tastan O. Discovering lncRNA mediated sponge interactions in breast cancer molecular subtypes. BMC Genomics. 2018; 19(1): 650.
  62. Luo D, Zou W, He Y, Xian H, Wang L, Shen J, et al. Modified dy­namic hip screw loaded with autologous bone graft for treating Pauwels type-3 vertical femoral neck fractures. Injury. 2017; 48(7): 1579-1583.
  63.  Zeng H, Fan X, Liu N. Expression of H19 imprinted gene in patients with repeated implantation failure during the window of implanta­tion. Arch Gynecol Obstet. 2017; 296(4): 835-839.
  64. Zuckerwise L, Li J, Lu L, Men Y, Geng T, Buhimschi CS, et al. H19 long noncoding RNA alters trophoblast cell migration and invasion by regulating TβR3 in placentae with fetal growth restriction. Onco­target. 2016; 7(25): 38398-38407.
  65. Xu J, Xia Y, Zhang H, Guo H, Feng K, Zhang C. Overexpression of long non-coding RNA H19 promotes invasion and autophagy via the PI3K/AKT/mTOR pathways in trophoblast cells. Biomed Phar­macother. 2018; 101: 691-697.
  66.  Zeng H, He D, Xie H, Zhao Y, Peng Z, Deng H, et al. H19 regulates angiogenic capacity of extravillous trophoblasts by H19/miR-106a- 5p/VEGFA axis. Arch Gynecol Obstet. 2020; 301(3): 671-679.
  67. Zhu Y, Liu Q, Liao M, Diao L, Wu T, Liao W, et al. Overexpres­sion of lncRNA EPB41L4A-AS1 induces metabolic reprogramming in trophoblast cells and placenta tissue of miscarriage. Mol Ther Nucleic Acids. 2019; 18: 518-532.
  68. Yang B, Zhang L, Cao Y, Chen S, Cao J, Wu D, et al. Overexpres­sion of lncRNA IGFBP4-1 reprograms energy metabolism to pro­mote lung cancer progression. Mol Cancer. 2017; 16(1): 154.
  69. Goda N, Ryan HE, Khadivi B, McNulty W, Rickert RC, Johnson RS. Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia. Mol Cell Biol. 2003; 23(1): 359-369.
  70. Camara AKS, Zhou Y, Wen PC, Tajkhorshid E, Kwok WM. Mito­chondrial VDAC1: a key gatekeeper as potential therapeutic target. Front Physiol. 2017; 8: 460.
  71. Zhang Y, Jin F, Li XC, Shen FJ, Ma XL, Wu F, et al. The YY1- HOTAIR-MMP2 signaling axis controls trophoblast invasion at the maternal-fetal interface. Mol Ther. 2017; 25(10): 2394-2403.
  72. Tseng JJ, Hsieh YT, Hsu SL, Chou MM. Metastasis associated lung adenocarcinoma transcript 1 is up-regulated in placenta previa in­creta/percreta and strongly associated with trophoblast-like cell in­vasion in vitro. Mol Hum Reprod. 2009; 15(11): 725-731.
  73. Che D, Fang Z, Mai H, Xu Y, Fu L, Zhou H, et al. The lncRNA ANRIL gene rs2151280 GG genotype is associated with increased susceptibility to recurrent miscarriage in a southern chinese popu­lation. J Inflamm Res. 2021; 14: 2865-2872.
  74. Holdt LM, Teupser D. Long noncoding RNA ANRIL: lnc-ing genetic variation at the chromosome 9p21 locus to molecular mechanisms of atherosclerosis. Front Cardiovasc Med. 2018; 5: 145.
  75. Pasmant E, Laurendeau I, Héron D, Vidaud M, Vidaud D, Bièche I. Characterization of a germ-line deletion, including the entire INK4/ ARF locus, in a melanoma-neural system tumor family: identifica­tion of ANRIL, an antisense noncoding RNA whose expression co­clusters with ARF. Cancer Res. 2007; 67(8): 3963-3969.
  76. Yu X, Zheng H, Chan MT, Wu WK. HULC: an oncogenic long non-coding RNA in human cancer. J Cell Mol Med. 2017; 21(2): 410- 417.
  77. Kong D, Wang Y. Knockdown of lncRNA HULC inhibits proliferation, migration, invasion, and promotes apoptosis by sponging miR-122 in osteosarcoma. J Cell Biochem. 2018; 119(1): 1050-1061.
  78. Ghafouri-Fard S, Taheri M. Maternally expressed gene 3 (MEG3): a tumor suppressor long non coding RNA. Biomed Pharmacother. 2019; 118: 109129.
  79. Zeng X, Hunt A, Jin SC, Duran D, Gaillard J, Kahle KT. EphrinB2- EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease. Trends Mol Med. 2019; 25(4): 265-286.
  80. Chen D, Teng JM, North PE, Lapinski PE, King PD. RASA1- dependent cellular export of collagen IV controls blood and lym­phatic vascular development. J Clin Invest. 2019; 129(9): 3545- 3561.
  81.  Xu C, Cui H, Li H, Wu Y, An H, Guo C. Long non-coding RNA ZEB2-AS1 expression is associated with disease progression and predicts outcome in gastric cancer patients. J BUON. 2019; 24: 663-671.
  82. Afonso S, Romagnano L, Babiarz B. The expression and function of cystatin C and cathepsin B and cathepsin L during mouse em­bryo implantation and placentation. Development. 1997; 124(17): 3415-3425.
  83. Thilaganathan B, Ralph E, Papageorghiou AT, Melchiorre K, Shel­don J. Raised maternal serum cystatin C: an early pregnancy marker for preeclampsia. Reprod Sci. 2009; 16(8): 788-793.
  84. Tang X, Gao Y, Yu L, Lu Y, Zhou G, Cheng L, et al. Correlations be­tween lncRNA-SOX2OT polymorphism and susceptibility to breast cancer in a Chinese population. Biomark Med. 2017; 11(3): 277- 284.
  85. Askarian-Amiri ME, Seyfoddin V, Smart CE, Wang J, Kim JE, Han­sji H, et al. Emerging role of long non-coding RNA SOX2OT in SOX2 regulation in breast cancer. PLoS One. 2014; 9(7): e102140.
  86. Brind J, Condly SJ, Lanfranchi A, Rooney B. Induced abortion as an independent risk factor for breast cancer: a systematic review and meta-analysis of studies on south asian women. Issues Law Med. 2018; 33(1): 32-54.
  87. Erlandsson G, Montgomery SM, Cnattingius S, Ekbom A. Abor­tions and breast cancer: record-based case-control study. Int J Cancer. 2003; 103(5): 676-679.
  88. Zhang M, Guo J, Liu L, Huang M, Li Y, Bennett S, et al. The role of long non-coding RNA, nuclear enriched abundant transcript 1 (NEAT1) in cancer and other pathologies. Biochem Genet. 2022; 60(3): 843-867.
  89. Mozdarani H, Ezzatizadeh V, Rahbar Parvaneh R. The emerging role of the long non-coding RNA HOTAIR in breast cancer develop­ment and treatment. J Transl Med. 2020; 18(1): 152.