MicroRNA Signature and Regulatory Functions in the Endometrium during Normal and Disease States

Pan Q, Qun Pan, Chegini N, Nasser Chegini
Seminars in reproductive medicine · 2008 · vol. 26(06) , pp. 479–493 · doi:10.1055/s-0028-1096128 · PMID:18951330 · PMC2728121 · W1986411911
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This review examines endometrial microRNA expression and regulatory roles in normal and disease states, exploring their potential for developing new therapies.

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The paper reviews and builds on the authors’ work characterizing microRNA (miRNA) expression in human endometrium and stromal/epithelial cells, focusing on how miRNAs regulate gene expression during normal versus abnormal uterine states. Using profiling of 287 miRNAs, the authors report 65 expressed in endometrium (32 differentially in stromal versus glandular epithelial cells) and show that ovarian steroids, specifically 17β-estradiol and progesterone, regulate a selected set of these miRNAs in isolated endometrial cells under defined conditions. A key theme is that miRNAs—including miR-20a, miR-21, miR-23, miR-26a, and others—are proposed to target networks involved in sex-steroid-responsive endometrial functions such as inflammation, immune regulation, apoptosis, cell cycle, and angiogenesis, with particular attention to miR-125b/miR-155 regulation by TNF-α and NF-κB, which may relate to dysfunctional bleeding. The authors explicitly limit conclusions because their initial endometrial profiling is restricted to early to mid-luteal phase tissues, when miRNA expression likely differs across the menstrual cycle. Relevance to endometriosis: the paper centers on endometrial miRNA regulation in inflammatory and dysfunction-associated bleeding contexts and cites dysfunctional uterine bleeding and endometrial abnormalities as related to altered inflammatory/repair processes that are mechanistically adjacent to endometriosis pathology.

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Abstract

During the menstrual cycle, human endometrium undergoes extensive cyclic morphologic and biochemical modifications in preparation for embryo implantation. These processes are highly regulated by ovarian steroids and various locally expressed gene products and involve inflammatory reaction, apoptosis, cell proliferation, angiogenesis, differentiation (tissue formation), and tissue remodeling. MicroRNAs (miRNAs) have emerged as key regulators of gene expression, and their altered and/or aberrant expression has been associated with establishment and progression of various disorders, including tumorigenesis. This review highlights the endometrial expression of miRNAs and their potential regulatory functions under normal and pathologic conditions such as endometriosis, dysfunctional uterine bleeding, and endometrial cancer. Given the key regulatory function of miRNAs on gene expression stability, understanding the underlying mechanisms of how endometrial miRNAs are regulated and identifying their specific target genes and their functions might lead to the development of preventive and therapeutic strategies by regulating specific target genes associated with such reproductive disorders.
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Mirna

Human embryo implantation is an extremely complex process, and the underlying mechanisms involved in this process and the establishment of maternal tolerance to the embryo remains incompletely understood. 1 , 5 , 7 , 28 , 38 , 101 – 104 It is clear that ovarian steroids and their receptors are essential for adequate endometrial receptivity. Evidence also indicates the requirement for several endometrium-derived autocrine/paracrine mediators for the establishment of an environment to allow for embryo implantation. Although the precise nature of the endometrial mediator(s) that distinguish this period is unknown, conventional and large-scale gene expression profiling has identified many candidate genes considered to play pivotal roles in this process. 1 , 5 , 7 , 38 , 101 , 102 , 104 Specific numbers of adhesion molecules and their receptors (integrins) important for the establishment of a direct dialogue between the embryo and the endometrium and several cytokines, growth factors, and chemokines are among these candidate genes. Although mice with targeted deletion of many of these genes do not exhibit any profound alterations in embryo implantation, lack of expression of some of these genes may influence other stages of embryo development. Functional redundancy among the biological actions of some of these factors may account for the mechanism of such activities. However, interruption in leukemia inhibitory factor (LIF) gene results in the failure of blastocyst implantation. In addition to adequate preparation of receptive endometrium, the establishment and maintenance of a viable embryo prior to reaching endometrium is essential for successful implantation. This is shown in part by the significant percentage of the embryos that reach the endometrium and do not implant. To gain insight into endometrial gene regulation during the embryo implantation period, many in vitro and in vivo animal models have been used. The results of these studies indicate to a complex microenvironment involving many specific genes highly regulated at transcriptional and translational levels. 1 , 5 , 7 , 38 , 101 , 102 , 104 Because of miRNA regulatory function in gene expression stability, a recent study by Chakrabarty et al illustrated the expression of a specific number of miRNAs during peri-implantation and preimplantation periods in mice, suggesting to serve as potential candidates relevant to embryo implantation. 100 Among the 32 miRNAs identified as relevant to embryo implantation, hsa-miR-101, hsa-miR-144, and hsa-miR-199a* are predicted to target cyclooxygenase-2 (COX-2) gene, which is considered to participate in events leading to peri-implantation and preimplantation embryo in mice. 100 The expression of these miRNAs correlated with the expression of COX-2 in the uterus during delayed implantation, further suggesting the potential regulatory function of these miRNAs on gene expression relevant to embryo implantation. The expression of COX-2 is regulated by a large number of growth factors, cytokines, and chemokines such as TNF-α and ovarian steroids. The expression of many of these mediators is targeted by miRNAs such as miR-125b and miR-155, 53 of which miR-155 expression was upregulated in day 4 (receptive) uteri. 100 Whether a feedback regulatory mechanism exists in coregulating the expression of miRNA-155 and target genes in the endometrium is yet to be determined; however, an increased endometrial expression of COX-2 and miR155 accompanied by a decrease in TNF-α expression during the receptive period support such interactions. In addition, TNF-α expression is targeted by miR-125b. 105 Other miRNAs whose profiles were identified as differentially expressed during peri-implantation and in day 4, day 5, and day 6 pregnant uteri in mice included hsa-let-7b, hsa-miR-19a, hsa-miR-127, hsa-miR-20a, hsa-miR-103, hsa-miR-199b, mmu-miR-201, hsa-miR-144, hsa-miR-512–3p, hsa-miR-195, hsa-miR-101, hsa-miR-199a*, hsa-miR-186, hsa-miR-17–3p, mmu-miR-291-5p, hsa-miR-181b, hsa-miR-96, hsa-miR-516–3p, hsa-miR-137, rno-miR-20*, hsa-miR-9*, mmu-miR-291-3p, and hsa-miR-302b. 100 Although many of these miRNAs are of human origin, their functional association during embryo implantation and early pregnancy in humans could only be predicted; however, because of their conserved homology among various species, they may function in similar manners. We have identified the expression of several of these miRNAs in human endometrium during the early to mid luteal phase, including the expression of let-7b, miR-19a, miR-20a, miR-199b, miR-101, miR-17-3p, miR-181b, as well as miR-125, miR-155, miR-26a, and miR-26b. 40 The miR-26 family has been predicted to target the expression of LIF among other genes. 106 , 107 Furthermore, the expression of miR-20a, miR-26a, miR-17–5p, miR-181, and miR-206 was the target of ovarian steroid regulatory actions in the endometrial epithelial and stromal cells. 40 These observations suggest that differential regulation of subsets of miRNAs may be required to stabilize the endometrial expression of specific genes critical for embryo implantation. However, detailed studies are needed to identify the specific endometrial genes targeted by these miRNAs and their associations with embryo implantation.

Mirnas

Considerable evidence exists implicating the altered expression of subsets of endometrial genes as hallmarks of establishment and progression of endometrial cancer, endometriosis, and dysfunctional uterine bleeding ( Fig. 2 ). They include ovarian steroid receptors, oncogenic and tumor suppressor genes, proinflammatory-and immune-related genes, angiogenic factors, progression cell-cycle related genes, and adhesion molecules and their receptors. 6 , 8 , 10 , 11 , 28 – 30 , 34 , 37 , 108 We provided evidence that the expression of subsets of miRNAs is altered in ectopic endometrium compared with paired eutopic or endometrium of women without endometriosis. Currently, there is no evidence indicating whether the expression of miRNAs in endometrial cancer differ from normal endometrium. However, considering the existence of different miRNA profiles in endometrium of women with endometriosis, it raises the possibility of differential expression profile in endometrial cancer compared with normal endometrium. Comparative analysis of the miRNAs expression among different endometrial abnormalities may allow for identification of specific miRNAs and their targeted genes associated with each disorder. Results of expression profiling generated from several cancer cells and tissues indicate considerable alterations in the expression of a large number of miRNAs compared with their normal cells and tissue counterparts. 44 , 109 – 116 In these studies, several oncogenes and tumor suppressor genes were identified and/or predicted as potential target of several miRNAs. 111 In most cases, association of miRNAs expression with tumorigenesis has been identified to be due to their ability to differentially regulate the expression tumor suppressor genes or oncogenes. 111 , 117 The expression of many of these oncogenes and tumor suppressor genes have also been associated with establishment and progression of endometrial cancer, 10 implying that miRNAs may serve in regulating their expression. Additionally, miRNA genes are frequently located at fragile sites and regions of loss of heterozygosity or common breakpoint regions. 109 , 111 Common fragile sites are large, genomically unstable regions, which are hot spots for deletions and other alterations, especially in cancer cells, including endometrial cancer cells. 118 In addition to oncogenes and tumor suppressor genes, miRNAs also target the expression of gene function as proinflammatory- and immune-related response, angiogenesis, cell-cycle progression, and adhesion molecule response. These processes are known to play a central role in various cellular activities critical to tumorigenesis, including endometrial cancer; they are also involved in pathogenesis of endometriosis and dysfunctional uterine bleeding. A considerable number of miRNAs predicted to target the expression of genes functioning as proinflammatory- and immune-related response, angiogenesis, cell-cycle progression, and adhesion molecules were expressed in eutopic and ectopic endometrium of women with endometriosis. The level of expression of these miRNAs in most instances was down regulated in the eutopic and ectopic endometrium of women with endometriosis as without endometriosis. 40 Although the expression of the genes targeted by specific miRNAs must be validated, the results suggest that ectopic endometrial tissues are programmed differently with respect to their gene expression regulation. Women with endometrial cancer, endometriosis, and more specifically contraceptive users often experience dysfunctional endometrial bleeding, which similar to normal menstruation is characterized by an increased inflammatory reaction and increased production of angiogenic mediators as well as excess production of proteolytic enzymes. 6 , 29 , 67 , 119 A detailed study involving miRNA expression profile at different stages of endometrial cancer and endometriosis as well as in women with dysfunctional bleeding would allow for better understating of the genes involved and establish the lineage and state of progression of these disorders. In addition, it would be of interest to determine whether the expression of miRNAs differs in normal menstruation compared with that in women experiencing dysfunctional uterine bleeding associated with contraceptive use. To provide some prospective of potential regulatory function of several miRNAs identified in normal endometrium and ectopic endometrium, we selected those whose expressions were confirmed in these tissues and isolated endometrial cells for further discussion. 40 Among these miRNAs, several are predicted to regulate the expression of angiogenic and proinflammatory- and immune-related genes, including let-7, miR-15, miR16, and miR-125. The expression of let7 family has been reported to be downregulated in several tumors and considered to serve as tumor suppressor. 120 – 122 Let-7 family clusters with miR-99/miR-100 and miR-125 family and is predicted to regulate inflammatory- and immune-related genes, cell-cycle progression, and apoptosis. 53 Additionally, miR-15a and miR-16–1 cluster is located at 13q14.3, a region that is deleted and/or downregulated in several disorders, with germ-line mutation identified in miR-16–1 precursor associated with low level of miR-16–1 expression in chronic lymphocytic leukemia. 123 The expression of miR-15a and miR-16–1 was also inversely correlated with Bcl-2 expression, 92 which is expressed in endometriosis and endometrial cancer tissues and may be the target of these miRNAs. Several studies have implicated ovarian steroids as regulators of endometrial cellular apoptosis through differential regulation of Bcl-2 and Bax expression. 6 Although ovarian steroids through differential regulation of miR-15 and miR-16–1 and other miRNAs could target the expression of apoptotic and antiapoptotic genes, it is also possible that differential regulation of inflammatory-related genes and their associated miRNAs account for promotion of apoptotic and antiapoptotic activities. Ovarian steroids regulate the expression and activation of c-myc in human endometrium and endometrial cancer, 124 and c-myc activation has been shown to increase the expression of the miR-17–92 cluster. 125 , 126 These observations have led to the suggestion that the miR-17–92 cluster in cooperation with increased c-myc expression results in accelerated tumor development. 125 , 126 These tumors established and developed earlier, were more aggressive, and had increased mitotic rate and less apoptosis compared with tumors generated with c-myc alone. The transcription factor E2F1 is also predicted as a target of the miR-17–92 cluster and transcriptionally regulated by c-myc. Regression of E2F1 expression has been shown to influence cell-cycle progression, and despite oncogenic activity, the miR-17-92 cluster can serve as tumor suppressor by decreasing E2F1 expression. 90 Unregulated expression of miR-221 and miR-222 promote cell growth by inhibiting p27, 127 and miR-27a suppresses the cdc2/cyclin B inhibitor Myt-1 in MDA-MB-231 cells promoting cell proliferation. 78 In the study of Kim et al, 128 they provided evidence that overexpression of miR-206 promotes cellular differentiation in C2C12 myoblasts. Detailed information implicating the regulatory function of miR-206 in gene expression is reviewed by Adams et al. 129 Interestingly, miR-206 also targets the expression of ERα in ER-positive breast cancer cells. 129 Altered expression of ERα as well as ERβ has been associated with several endometrial disorders, including endometrial caner, endometriosis, and dysfunctional uterine bleeding. 130 – 132 We demonstrated that ovarian steroids regulate the expression of miR-206 in endometrial epithelial and stromal cells and their actions were in part altered by estrogen and progesterone antagonists ICI-182780 and RU486, respectively. Selective estrogen and progesterone receptor modulators and estrogen and progesterone antagonists have been demonstrated to effectively regress the growth of endometrial implants in animal models of endometriosis, in clinical trials in humans, and of endometrial cell growth in vitro. These observations suggest that estrogen and progesterone antagonists may target the endometrial expression of miRNAs resulting in a reprogramming of their target genes expression. Detailed studies are needed to determine the molecular mechanisms by which these agents influence the expression of miRNAs and their target genes.

Potential

Upon the establishment of regular ovulatory cycles, the endometrium under the influence of sex steroids undergoes substantial cyclic morphologic and biochemical changes. Estrogen acts as a mitogen for various endometrial cells, and progesterone acting on the estrogen-primed endometrium induces differentiation and secretory changes in the glandular epithelial cells. Although the mid–luteal phase rise in estrogen is not essential for successful embryo implantation, 26 , 27 the uterus retains its responsiveness to sex steroid hormones, and endometrial cycles can be induced to become receptive for embryo implantation even after menopause. 28 Progesterone also causes stromal decidualization and prepares the endometrium for embryo implantation, and a sudden decline in sex steroids production at the end of luteal phase initiates normal menstrual bleeding. 6 , 29 , 30 Estrogen and progesterone mediate their actions through estrogen receptors (ERs) and progesterone receptors (PRs), respectively. These receptors are ligand-activated transcription factors, and their activation leads to regulation of expression of their target genes in cell- and promoter-specific manners in ovarian steroid sensitive tissues, including the endometrium. Accumulated evidence supports the expression and regulatory function of many gene products in the endometrium throughout the menstrual cycle under normal and pathologic conditions. 5 , 6 , 11 , 28 , 31 – 34 The expression of these genes, which include many inflammatory and immune mediators, fibrinolytic and proteolytic enzymes, cell-cycle and apoptotic regulators, extracellular matrix, adhesion molecules, and angiogenic factors and their receptors, are differentially regulated during the menstrual cycle as part of preparation for endometrial degenerative and reparative processes. 1 – 7 These intrinsic molecules are expressed and released by activated platelets, inflammatory and immune-related cells infiltrating into the endometrium, as well as by endometrial epithelial, stromal, and vascular endothelial cells. Altered endometrial expression of these molecules seems to be responsible for inappropriate tissue regeneration, resulting in dysfunctional uterine bleeding, failure in embryo implantation, as well as many other endometrial disorders. 1 , 5 , 6 , 8 – 11 , 31 , 34 – 39 Gene expression is regulated at multiple levels, including at transcriptional and translational levels and influenced by miRNA regulatory functions. Although the field of miRNA research has rapidly evolved during the past few years, only limited information is currently available for their expression and functions in human reproductive tract tissues. Given the key regulatory function of miRNAs in gene expression, it is pivotal to define their expression and their underlying mechanism of actions and regulation in these tissues. It is also essential to identify the specific genes relevant to endometrium targeted by these miRNAs at various stages of normal menstrual cycle and associated abnormalities. We have recently reported the expression profile of a few hundred miRNAs in human endometrium and endometrial stromal and epithelial cells. 40 Of the 287 human miRNAs profiled, we identified the expression of 65 miRNAs in the endometrium, of which 32 were differentially expressed in endometrial stromal and glandular epithelial cells isolated from the same tissues. Such a sharp reduction in expression of a large number of miRNAs in isolated endometrial cells implies the importance of endometrial microenvironment on regulation of miRNA expression. The decline in the number of miRNAs expressed in the endometrial cells compared with their original tissues also reflects possible regulatory function of ovarian steroids or many locally expressed mediators on the expression of these miRNAs by various endometrial cells. However, our study was limited to endometrial tissues of the early to mid luteal phase of the menstrual cycle to draw any specific conclusion, as the profile of miRNA expression most likely differs in endometrium from other phases of the menstrual cycle. To provide support for the influence of ovarian steroids, we used isolated endometrial cells cultured under defined conditions and identified the regulatory action of ovarian steroids on the expression of a selected number of these miRNAs. 40 Among the miRNAs regulated by 17β estradiol and progesterone in the endometrial epithelial and stromal cells are miR-20a, miR-21, miR-23, miR-26a, miR-18a, miR-181a, miR-206, and miR-142-5p. 40 These miRNAs have been predicted to target the expression of a large number of genes, including transforming growth factor, β (TGF-β), TGF-β receptors, ERs, PRs, and CYP-19A1 (aromatase), many of which are known to play critical roles in endometrial activities. 40 We are further investigating the expression of specific genes targeted by these miRNAs in the endometrial cells with the aim of identifying the mechanism by which these miRNAs regulate gene expression relevant to the endometrium. Accumulated evidence has been generated in support of the expression of miRNAs in various cells and tissues under normal and disease conditions. 15 , 40 – 44 Recent functional analysis of several miRNAs has revealed their key regulatory influence of the expression of target genes involved in various cellular activities under normal physiologic and disease conditions, more specifically developmental processes and tumorigenesis. 15 , 40 – 43 In particular, miRNAs target the expression of genes involved in cell-cycle progression, differentiation, apoptosis, inflammatory and immune response, and angiogenesis ( Fig. 1 ). 42 , 44 – 48 These cellular processes are integrated in parts of the endometrial regeneration throughout the menstrual cycle that are regulated by sex steroids and a vast number of gene products whose expression may be the target of miRNA regulatory functions.

Conclusions

The unprecedented advancements in molecular biological approaches during the past decade have led to the identification of the expression of many genes in the endometrium under normal and diseased conditions. The product of some of these genes acting in an autocrine/paracrine and interactive manners are known to regulate many events such as inflammatory and immune responses, cell-cycle progression, differentiation, apoptosis, and tissue remodeling. Precise regulation of the expression of these genes is fundamental in directing these processes for normal endometrial functions. Unregulated expression of some of these genes appears to account for various endometrial abnormalities including infertility, endometriosis, and endometrial cancer. Clearly, ovarian steroids through their ability to regulate the expression of many of these genes at transcriptional and translational levels play central roles in endometrial biological and physiologic integrity. Micro-RNAs have emerged as important regulators of gene expression. These small, non–protein-coding RNAs through complementary interactions with their predicted target genes regulate their expression mostly through transcriptional and translational regression. 133 Expression profiling and cloning strategies have identified a large number of miRNAs in various cells and tissues under normal and disease conditions. Functional analysis also revealed that miRNAs can potentially target the expression of a third or possibly more of the genes in humans. Current evidence for the expression, regulation, and function of miRNAs in human reproductive tract tissues is limited to a few studies. The expression profile of a few hundred miRNAs in the endometrium and endometrial cells and their aberrant expression in ectopic endometrium in women with endometriosis support their key biological relevance. Additionally, ovarian steroids appear to regulate the expression of miRNAs in endometrial cells; however, the specific pattern of their expression throughout the menstrual cycle remains to be elucidated. It is also necessary to verify and correlate the expression of genes targeted by differentially expressed miRNAs in the endometrium and to determine whether their profiles and targeted genes expression differ in endometrial disorders such as endometrial cancer and dysfunctional uterine bleeding compared with that of normal endometrium. This is particularly important because expression profiling of miRNAs appears to be far more superior to mRNA expression profiling to differentiate normal from diseased tissues. If such a pattern of miRNA expression could differentiate normal endometrium from diseased conditions, the result may have a significant impact on prognostics and diagnostics approach as a useful tool for assessing response to various treatment strategies. In addition, miRNAs that are aberrantly expressed in any of the endometrial disorders could be effectively targeted by their complementary anti-miR and/or pri-miR oligonucleotides for loss of function and gain of function. As such, evidence generated in other cell and in vivo systems supports their experimental use for therapeutic application and management of disorders such as lowering of plasma cholesterol (miR-122), cancer therapy (miR-21), cardiac hypertrophy (miR-21), and cardiac arrhythmia (miR-1). Collectively, extensive basic and transitional research is needed to improve our basic knowledge of endometrial miRNAs expression, regulation, and functions under normal and diseased conditions to allow for identification of potent therapeutic applications for miRNAs.

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endometriosis

MeSH descriptors

Endometrium Gene Expression Profiling Gene Expression Regulation MicroRNAs MicroRNAs Uterine Diseases Apoptosis Apoptosis Embryo Implantation Embryo Implantation Endometrium Endometrium Female Humans Inflammation Inflammation MicroRNAs MicroRNAs Models, Biological Neovascularization, Physiologic

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