{"paper_id":"5987e1f7-7af6-491b-bfbf-7f77a7bd8674","body_text":"Effective pregnancy implantation relies on a complicated molecular cross-talk between\nthe mother’s uterus and the developing conceptus. In pigs, maternal and fetal\ncontact occurs approximately three times on the 12 th  day of pregnancy.\nImplantation in pigs is associated with the dynamic production of estrogen,\nprogesterone, prostaglandins, adhesion molecules, and immune factors. To achieve\nsuccessful implantation, suitable endometrium, embryo quality, and molecular\ncellular changes in the uterine environment are required. The most crucial factor is\nthe receptive endometrium, which undergoes significant cellular and molecular\nchanges from non-receptive to receptive. If the endometrium is not receptive, the\nblastocyst cannot be implanted ( Evans  et\nal.,  2016 ).\nThe human endometrium as a dynamic tissue experiences regular regeneration during the\nmenstrual cycle, and the uterus is receptive to embryo implantation for only a short\nperiod ( Gellersen  et al., \n2007 ;  Evans  et al., \n2016 ). It has been estimated that 1.3% of implantation failures in\nhealthy women result from the non-acceptance of endo-metrial tissue ( Altmäe  et al.,  2017 ). In\npatients undergoing in vitro fertilization (IVF) cycles, 60 to 70% of patients with\nhigh embryo quality cannot implant successfully due to non-receptive endometrium\n( Paulson  et al.,  1997 ;\n Heng  et al.,  2011 ).\nTherefore, awareness of the endometrial receptivity molecular regulation is\nessential in increasing implantation rates and fertility therapy.\nEndometrial remodeling varies between human species (menstrual cycle) and animals\n(estrous cycle) ( Johnson, 2018 ;  Shekibi  et al.,  2022 ). It is\nalso known that changes in the cellular and molecular levels of the uterine\nenvironment can affect endometrial receptivity ( Salamonsen  et al.,  2009 ;  Lessey & Young, 2019 ;  Ochoa-Bernal & Fazleabas, 2020 ).\nBiochemically, invasion mechanisms involved in embryo implantation include apoptosis\nand other mechanisms for epithelial breakdown, cell-cell or cell-substrate\ninteractions that contribute to migration, vascular and extracellular matrix (ECM)\nremodeling, as well as immune responses involving adaptive and innate immune cells\n( Hernández-Vargas  et\nal.,  2020 ). Despite advances in assisted reproductive\ntechnology (ART), knowledge about embryo implantation remains incomplete. The\ncellular and molecular changes in endometrial tissue are the most important factors\nin the success or failure of embryo implantation. Identifying biomarkers to improve\nthe chances of pregnancy in ART cycles is crucial. Although studies on small\nmolecules have shed some light on the mechanism of embryo implantation failure,\nthere has not been an improvement in the pregnancy rates and implantation of\nclinical embryos. Thus, new methods are essential to enhance embryo implantation\nefficiency.\nLong non-coding RNAs (lncRNAs) as RNA transcripts have more than 200 nucleotides with\nno or little protein-coding capacity without an effective open reading frame. They\nhave been considered in the past few years and have functional roles in chromatin\nmodification, epigenetic regulation, transcriptional control, genomic imprinting,\nand pre- and post-translational mRNA processing. LncRNAs similar to mRNAs can be\ntranscribed by spliced, RNA polymerase II, polyadenylated, and presumably capped at\nthe 5’ ends ( Li  et al., \n2019 ).\nIn this review, we discuss the lncRNAs that are effective in endometrial receptivity\nand their potential use as therapeutic target biomarkers in human fertility\ntreatment. Abnormalities in lncRNA profiles can significantly affect the\nimplantation ability of uterine tissues, which can be one of the important causes of\nendometrial receptivity disorder.\n\nThe first stage of the menstrual cycle is the follicular or proliferative\nphase. It occurs from the first day to the 14 th  day of the\nmenstrual cycle, based on an average duration of 28 days. Changes in the\nlength of the menstrual cycle occur due to changes in the length of the\nfollicular phase. The main hormone in this phase is estrogen, especially\n17-beta estradiol. The increase of this hormone occurs by regulating the FSH\nreceptors in the follicle at the beginning of the cycle. However, as the\nfollicular phase progresses to the end, increased amounts of\n17-beta-estradiol provide negative feedback to the anterior pituitary. The\npurpose of this stage is the growth of the endometrial layer of the uterus.\n17-beta-estradiol achieves this by increasing the growth of the endometrial\nlayer of the uterus, stimulating increased amounts of stroma and glands, and\nincreasing the depth of the arteries that supply the endometrium, the spiral\narteries. 17-Beta-estradiol achieves this by creating channels in the\ncervix, allowing sperm to enter ( Herbison,\n2020 ). During this stage, a primordial follicle begins to mature\ninto a Graafian follicle. The surrounding follicles begin to degenerate,\nthis is when the Graafian follicle becomes the mature follicle. This sets\nthe follicle up for ovulation ( Stankewicz\n et al.,  2024 ).\nOvulation always occurs 14 days before menstruation. Therefore, with an\naverage cycle of 28 days, ovulation occurs on day 14. At the end of the\nproliferative phase, the level of 17-beta-estradiol is at a high level due\nto follicle maturation and increased hormone production. Only during this\ntime, 17-beta-estradiol provides positive feedback for the production of FSH\nand LH. This occurs when a critical level of 17-beta-estradiol is reached,\ni.e. at least 200 pg/ml of plasma. The high levels of FSH and LH present at\nthis time is called the LH surge. As a result, the mature follicle ruptures,\nand an egg is released ( Stankewicz\n et al.,  2024 ).\nThis phase always occurs from day 14 to day 28 of the cycle. Progesterone\nstimulated by LH is the dominant hormone at this stage to prepare the corpus\nluteum and endometrium for the implantation of a possible fertilized egg. As\nthe luteal phase ends, progesterone provides negative feedback to the\nanterior pituitary to decrease FSH and LH levels and subsequently\n17-beta-estradiol and progesterone levels. The corpus luteum is a structure\nformed in the ovary at the site of mature follicle rupture and produces 17\nbeta-estradiol and progesterone, which is dominant at the end of the phase\ndue to the negative feedback system. The endometrium is prepared by\nincreasing vascular reserve and stimulating mucous secretions. This is\nachieved by stimulation of the endometrium by progesterone to slow down the\nproliferation of the endometrium, reduce the thickness of the lining,\ndevelop more complex glands, accumulate energy sources in the form of\nglycogen, and create more surface area inside the spiral arteries. Near the\nend of the secretory phase, plasma levels of 17-beta-estradiol and\nprogesterone are produced by the corpus luteum ( Bajpai  et al.,  2023 ) ( Figure 1 ).\nFigure 1 (A) Endometrial changes across the menstrual cycle in humans. (B)\nEndometrial changes across the Estrus cycle.\n(A) Endometrial changes across the menstrual cycle in humans. (B)\nEndometrial changes across the Estrus cycle.\nWhen the hormone level decreases, the endometrial layer, as it has changed\nduring the menstrual cycle, is not able to maintain. This is called\nmenstruation, which is considered to be days 0 to 5 of the next menstrual\ncycle. Menstrual blood is mainly arterial and only 25% of blood is venous.\nIt contains prostaglandins, tissue debris, and relatively large amounts of\nfibrinolysis from endometrial tissue. The normal duration of menstruation is\n3 to 5 days, but menstruation as long as 1 day and up to 8 days can occur in\na normal woman ( Bajpai  et\nal.,  2023 ).\nNon-coding RNAs are one of the epigenetic modifications that regulate endometrial\ndecidualization. LncRNAs exhibit very low species conservation amongst various\nspecies with high specificity in various cells and tissues ( Li & Chang, 2014 ). They are involved in\nnormal biological processes as well as the development and occurrence of complex\nillnesses ( Bartonicek  et al., \n2016 ;  Schmitz  et\nal.,  2016 ).\nThe regulation of lncRNAs in human endometrial decidualization has recently been\nconsidered. Earlier studies revealed significant expression of lncRNAs in hESCs\nfrom patients with diverse diseases ( Monnier\n et al.,  2013 ;  Ghazal  et al.,  2015 ;  Fan  et al.,  2017 ;  Wang  et al.,  2018 ;  Chen  et al.,  2019 ). Subsequently, relevant\nstudies have delved into the regulatory mechanisms of lncRNAs during endometrial\ndecidualization ( Liang  et al., \n2016 ;  Zhao  et al., \n2022a ). However, the regulatory mechanism of ln-cRNAs in the\npathological state’s abnormal decidualization of the endometrium remains\nunclear. lncRNAs participate in regulating various biological processes,\nincluding carcinogenesis, epigenetic regulation, and embryonic development\n( Wapinski & Chang, 2011 ;  Subramanian  et al.,  2013 ).\nIt is attempted to identify important lncRNAs as biomarkers to anticipate\nendometrial receptivity ( Koot  et\nal.,  2016 ;  Sigurgeirsson\n et al.,  2017 ;  Vireque  et al.,  2017 ;  Feng  et al.,  2018 ;  Chen  et al.,  2019 ). lncRNA expression has\nbeen characterized in the female reproductive tract, particularly during the\nperi-implantation period when expressed in the uterus.\nOne of the essential criteria for successful implantation is the quality of the\nendometrial tissue and its epithelial and stromal cells, which are in direct\ncontact with the blastocyst. Decidualization should occur efficiently for\nimplantation to progress. The role of lncRNAs in humans in implantation progress\nhas been studied. The endometrium can also be affected by embryo implantation\n( Zhao  et al., \n2022a ; b ). Due to the\nincreasing application of IVF methods, spent blastocyst cultures have been\nanalyzed for lncRNA and other biomarkers ( Azevedo-Quintanilha  et al.,  2019 ).\nWhile previous reviews on lncRNAs and embryos often discussed embryo development\nas well as implantation, some studies have noted that lncRNAs secreted by\npre-implantation blastocysts can facilitate embryo-endometrial communication to\nimprove implantation. However, we did not explain this issue here in detail.\nEmbryo-derived ln-cRNAs also play a role in implantation failure.\nUnlike mRNA, which acts based on RNA strand modifications to increase its\nstability ( Azevedo-Quintanilha  et\nal.,  2019 ), lncRNAs are not directly translated into\nprotein ( Spizzo  et al., \n2012 ;  Tahermanesh  et\nal.,  2023 ). Many studies have shown that lncRNAs play\nvital roles in several biological processes using mechanisms, like genetic\nimprinting, mRNA degradation, chromatin remodeling, mRNA editing, splicing\nregulation, and translation regulation ( Geisler\n& Coller, 2013 ;  Zhu  et\nal.,  2013 ). Examples of such lncRNAs are shown in  Table 1 .\nIdentification of LnCRNAs involved in implantation.\nIn human endometrial tissue, the expression of  TCONS_01729386 \nincreases the expression of Fibroblast Growth Factor 7  (FGF7), \nNeuromedin B  (NMB),  fibroblast growth factor-9\n (FGF9),  Vascular Endothelial Growth Factor C (VEGFC),\nVascular Endothelial Growth Factor A  (VEGFA),  Mucin 1\n (Muc1),  Estrogen Receptor 1  (ESR1),  and\nRetinol Binding Protein 4  (RBP4)  genes ( Wang  et al.,  2016 ), while\n TCONS_01325501  also increases the expression of these genes\n( Wang  et al.,  2016 ).\nAccording to microarray studies, it has been proven that when the expression of\nthese genes increases, the rate of implantation increases ( Herington  et al.,  2016 ). These genes help\nto improve implantation by increasing the rate of angiogenesis, proliferation,\nand invasion, and reducing apoptosis ( Herington\n et al.,  2016 ).\nAdditionally, gi|672027621 decreases Pyrimidinergic Receptor P2Y6\n( P2ry6 ) expression, while\n gi | 672045999  reduces A disintegrin and\nmetalloproteinase with thrombo-spondin motifs 7  (Adamts7 )\nexpression and improves implantation ( Cai\n et al.,  2019 ). Furthermore, in endometrial\ntissue, the expression of  lncRNA-  matrix metalloproteinase-11\n (MMP11)  increases the expression of  MMP11 \n( Zhao  et al., \n2022a ; b ; c ), and  lncRNA-TCL6  decreases\n Epidermal growth factor receptor (EGFR),  extracellular\nsignal-regulated kinases ( ERK ), and  AKT  gene\nexpression in human endometrial tissue ( Liu\n& Gong, 2018 ). These genes help to improve implantation by\nincreasing the rate of proliferation, and invasion and reducing apoptosis ( Herington  et al., \n2016 ).\nCCDC144NL-AS1  decreases  MMP9  expression in\nendometrial tissue ( Zhang  et\nal.,  2018 ), while H19, by affecting lethal-7\n (Let  7), decreases Integrin alpha-IIb/beta-3\n (ITGB3)  gene expression and reduces the implantation rate\nin human endometrial tissue ( Zeng  et\nal.,  2017 ).  ITGB3  helps to improve\nimplantation by increasing the rate of angiogenesis ( Herington  et al.,  2016 ).\nIn epithelial cells of human endometrial tissue, the expression of  lncRNA\nT-Cell Leukemia/Lymphoma 1  ( TCL1 ) and five prime\nto Xist ( FTX ) increases the expression of\n TUNAR  and  E-cadherin,  respectively, while\ndecreasing the expression of  N-cadherin, vimentin,  and zinc\nfinger E-box binding homeobox 1, thereby improving implantation ( Wang  et al.,  2020a ; b ). Meanwhile, in human epithelial cells,\nthe expression of  PTENP1  increases the expression of\n miR-590-3p  and destroys implantation ( Takamura  et al.,  2020 ), These genes help\nto improve implantation by increasing the cell mobility and decidualization in\ncell endometrium ( Wu  et al., \n2023 ).\nIn human stromal cells, the expression of  lncRNA TCL1  increases\nTCL1 Upstream Neural Differentiation-Associated RNA  (TUNAR) \nexpression ( Wang  et al., \n2020b ), while  lncRNA FTX  increases the expression of\nE-cadherin and decreases the N-cadherin, zinc finger E-box binding homeobox 1\nand vimentin expression, thereby improving implantation ( Wang  et al.,  2020a ). On the other hand,\n lncSAMD11-1:1  downregulates\nPhosphatidylinositol-5-Phosphate 4-Kinase Type 2 Alpha\n( PIP4K2A ) expression ( Zhang\n et al.,  2022 ), and\n NONHSAT083203.2  increases Cat Eye Syndrome Chromosome\nRegion, Candidate 3 ( CECR3 ) expression, impairing implantation\n( Feng  et al.,  2018 ).\nAdditionally,  NON-HSAT212577.1, NONHSAT035952.2, NONHSAT193031.1,\nNONHSAT053761.2,  and  NONHSAT025064.2  increase the\nexpression of ST7 Overlapping Transcript 3  (ST7-OT3),  DHRS4\nAntisense RNA 1  (DHRS4-AS1  ), chromosome 22 open reading frame\n34  (C22orf34),  RAMP2 Antisense RNA 1\n (RAMP2-AS1)  gene, and  PNCT_HSA157732, \nrespectively, in human stromal cells ( Feng\n et al.,  2018 ).\nFinally, the expression of  H19  decreases Insulin-like growth\nfactor-binding protein 1  (IGFBP1  ) expression in human\nendometrial tissue ( Ariel  et\nal.,  1997 ;  Adriaenssens\n et al.,  1999 ;  Kallen  et al.,  2013 ). while\n LINC473  decreases the expression of Prolactin\n( PRL ),  IGFBP1,  Progesterone receptor\n( PGR ), Forkhead box protein O1 ( FOXO1 ),\nand Homeobox A10 ( HOXA10 ) in human stromal cells ( Chau  et al.,  2002 ).\n HOXA11  antisense expression in endometrial stromal cells\ndecreases  HOXA11  expression and impairs implantation ( Chau  et al.,  2002 ). These\ngenes help to improve implantation by increasing the proliferation in cell\nendometrium ( Binart  et al., \n2010 ).\nIn human serum, the expression of HIF-1alpha ( aHIF ) increases\n VEGF  expression and impairs implantation ( Qiu  et al.,  2019 ), VEGF\nhelps to improve implantation by increasing the rate of angiogenesis, and\nproliferation ( Herington  et\nal.,  2016 ) ( Table\n1 ).\nThe first successful IVF birth was reported in 1978 ( Steptoe & Edwards, 1978 ), and since then, over eight\nmillion cases have been born through assisted reproductive methods, which have\nbecome popular worldwide ( Edwards, 2005 ;\n Kamel, 2013 ). However, as previously\nstated, implantation failure can limit IVF therapy, which is mainly caused by\ninsufficient endometrial receptivity. LncRNAs are important players in\nestablishing endometrial receptivity, and their presence in serum is useful to\ndiagnose receptivity and fertility ( Feng\n et al.,  2018 ;  Wang  et al.,  2020b ). Furthermore, as lncRNAs are\nbeing used as therapeutics in clinical trials in other fields ( Bouckenheimer  et al.,  2016 ;\n Feng  et al.,  2018 ),\ntheir potential use in endometrial preparation in IVF is also being explored.\nThe identification of LncRNAs can help in the development of diagnostic kits\nthat may become predictive biomarkers for endometrial receptivity.\nThe majority of lncRNA therapeutic trials are today based on their inhibition of\nmiRNAs or activation of genes ( Chen,\n2015 ). However, it is possible to register both as one patent. While most\nstudies have focused on the therapeutic effect of lncRNAs on cancer, no drugs\nwith lncRNA activating or inhibiting properties have been developed yet.\nNevertheless, ongoing studies on the identification of lncRNAs related to\ninfertility primarily target endometrial tissue. Currently, there are no lncRNA\ntherapeutic drugs in clinical trials, and several technologies are involved in\nthe transfer of lncRNA, with most being used to inhibit miRNAs. One of these\ntechniques is nanotechnology and artificial exogenous extracellular vesicles\n(EVs), which facilitate the transfer of active or inhibiting lncRNA drugs to the\ntarget tissue ( Wu  et al., \n2021 ).\n\nSeveral research efforts have performed genome-wide analyses of differentially\nexpressed lncRNAs in tissue, endometrial-derived cells, and women’s serum. Although\ndifferential expression of hundreds of lncRNAs has been reported, their roles are\nunclear. For example, 516 differentially expressed lncRNAs were reported by RNA\nsequencing assessment of human endometrial tissue derived from women with normal\ncycles during the secretory and proliferative stages, especially the implantation\nwindow ( Sigurgeirsson  et al., \n2017 ). Among the most expressed lncRNAs, nuclear-enriched abundant\ntranscript 1 ( NEAT1 ) can be mentioned ( Sigurgeirsson  et al.,  2017 ). However, the\nfunctional role of lncRNAs in the menstrual cycle cannot be understood only by the\nidentification of differentially expressed lncRNA. Characterization assessments\nshould be done to understand the functional and physiological roles of such lncRNAs\nin the endometrium.\nBiomarkers capable of improving the embryo implantation success rate following IVF\nprocedures should be identified and the prognosis and diagnosis of endometrial\npathologies should also be considered. With increasing knowledge on the role and\nregulation of lncRNAs in the endometrium deepens, we can expect to gain a better\nunderstanding of the normal and abnormal physiology of the endometrium, resulting in\nnovel diagnostics and therapies according to the biological feature of such\nregulatory RNAs.","source_license":"public-domain-us","license_restricted":false}