Reproductive and Developmental Medicine

REVIEW ARTICLE
Year
: 2019  |  Volume : 3  |  Issue : 4  |  Page : 247--251

Endometriosis pathoetiology: The role of micrornas in the dysregulation of endometrial functions


Jiahui Zhang1, Isabelle Baptista2, Ping Xia3, Bhuchitra Singh4,  
1 Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA
2 Johns Hopkins University, Baltimore, MD 21205, USA
3 Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Department of Gynecology and Obstetrics, Division of Reproductive Sciences and Women's Health Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

Correspondence Address:
Bhuchitra Singh
Department of Gynecology and Obstetrics, Division of Reproductive Sciences and Women's Health Research, Johns Hopkins School of Medicine, 720 Rutland Avenue, Ross Research Building, Room No. 624, Baltimore, MD 21205
USA

Abstract

Endometriosis is a common gynecological disorder characterized by pelvic pain, heavy menstruation, and infertility. The clinical diagnosis of endometriosis is often delayed 8–10 years after the onset of symptoms due to the lack of an effective and reliable noninvasive diagnostic method. In recent years, a number of research studies have reported using microRNAs (miRNAs) as potential noninvasive biomarkers for diagnosing endometriosis. Because miRNAs regulate gene expression, the differential expression of miRNAs in endometriosis patients also provides insight on dysregulated gene expressions in the pathogenesis of endometriosis. In this review, a number of global profiling studies (published through July 2019) that investigated the differential expression of miRNAs in endometriosis were identified. Based on these findings, the role of miRNAs in the pathogenesis of endometriosis, particularly with regard to the dysregulation of endometrial functions, cell cycle regulation, proliferation of endometrial stromal cells, and angiogenesis, was discussed. The potential of these miRNAs as noninvasive diagnostic biomarkers of endometriosis was also discussed.



How to cite this article:
Zhang J, Baptista I, Xia P, Singh B. Endometriosis pathoetiology: The role of micrornas in the dysregulation of endometrial functions.Reprod Dev Med 2019;3:247-251


How to cite this URL:
Zhang J, Baptista I, Xia P, Singh B. Endometriosis pathoetiology: The role of micrornas in the dysregulation of endometrial functions. Reprod Dev Med [serial online] 2019 [cited 2020 Jun 5 ];3:247-251
Available from: http://www.repdevmed.org/text.asp?2019/3/4/247/274551


Full Text



 Introduction



Endometriosis, a common gynecological disorder characterized by pelvic pain, heavy menstruation, and infertility, affects 6%–10% of reproductive-age women.[1] Currently, the diagnosis of endometriosis is made primarily through clinical evaluations such as laparoscopy and pelvic examinations. Due to the lack of an effective and reliable noninvasive diagnostic method, endometriosis is often not diagnosed until severe symptoms have developed, usually 8–10 years after the onset of symptoms.[2],[3] Although numerous biomolecules have been recognized to be expressed at abnormal levels in women with endometriosis, a unique biomarker that can be used to reliably diagnose endometriosis remains to be found.

One ongoing area of research is the potential of microRNAs (miRNAs) as diagnostic markers for endometriosis. miRNAs are small (~22 nucleotide), highly conserved, noncoding RNAs that regulate gene expression.[4] Most miRNAs are thought to negatively regulate gene expression by posttranscriptional repression or degradation, but research has shown that translational activation by miRNA also occurs.[5] It has been reported that miRNAs are expressed differently in the endometrium of women with endometriosis compared to those without.[6] Because the differential expression of miRNA indicates dysregulated gene expression, miRNA profiling in endometriosis patients will likely be useful in elucidating the pathogenesis of the disease. A systematic search was performed on PubMed using keywords “endometriosis,” “microRNA,” “miRNA,” and “biomarkers.” Studies published between 2007 and July 2019 on the role of miRNAs in endometriosis were identified and screened based on study methods and major findings. The differential expression of miRNAs in endometriosis and their potential as biomarkers of endometriosis were discussed based on these findings. The key miRNAs found to be differentially expressed in endometriosis as well as their proposed functions and target genes are summarized in [Table 1].{Table 1}

 Cell Cycle Dysregulation and Progesterone Resistance



Endometriosis is characterized by estrogen dependence and progesterone resistance. Burney et al. used array-based, global miRNA profiling to study progesterone resistance in early secretory (ES)-phase eutopic endometrium in women with endometriosis.[7] A previous transcriptomics analysis by Burney et al. had demonstrated that dysregulation of numerous genes in the cell cycle pathway led to the maintenance of the proliferative phase in ES endometrium in women with endometriosis, consistent with its characteristic progesterone resistance.[8] In a recent study, comparison of ES endometrium from healthy controls versus women with moderate-to-severe-stage endometriosis demonstrated differential miRNA expression.[7] Although the majority of miRNAs remained unchanged, a total of six miRNAs in the miR-9 and miR-34 families were found to be downregulated in endometriosis. Recent studies have investigated the role of miR-9 in regulating apoptosis by targeting BCL2, an anti-apoptotic protein overexpressed in the ES endometrium of women with endometriosis.[8],[9] Previous research has provided evidence that miR-9 is dysregulated in recurrent ovarian cancer, in which it may act as a tumor suppressor gene.[10] The miR-34 family is known to be mediators of p53-dependent suppression of proliferation.[11] The downregulation of these miRNAs in endometriosis may, therefore, be associated with the maintenance of the proliferative phase in ES endometrium.[7]

A similar study by Joshi et al. found that miR-29c may be another miRNA that contributes to progesterone resistance in endometriosis.[12] In their experiment, which tested eutopic endometrial tissue from baboons and women with deep-invasive endometriosis (DIE), the expression of miR-29c was found to be increased, while the levels of its target transcript, FK506-binding protein 4 (FKBP4), were decreased. The authors thus concluded that the increase in miR-29c expression may contribute to progesterone resistance by decreasing FKBP4 levels and that resection of the DIE tissue is likely to reverse the progesterone resistance associated with endometriosis.[12]

Several other miRNAs have been identified in endometriosis that are linked to the p-53 pathway or cell cycle regulation. A study by Cho et al. comparing circulating miRNA in serum samples of women with and without endometriosis found that miRNAs miR-135b, let-7b, let-7d, and let-7f were all expressed at lower levels in patients with endometriosis.[13] The study found a strong negative correlation between serum levels of let-7b and CA-125, which is a known biomarker for endometriosis. As several of the let-7b's target sites, such as CCND1, CCND2, and CDKN1A, are involved in the p53 signaling pathway and cell signaling, the authors interpreted that the role of let-7b in endometriosis may involve dysregulation of the p53 pathway or cell cycle control.[13] This corresponds to previous findings that a polymorphism in a let-7b binding site of KRAS leads to abnormal endometrial KRAS expression and increased proliferation.[14] Cho et al. also found that miR-135a expression was downregulated in the serum of patients with endometriosis, although previous studies have reported the overexpression of miR-135a and miR-135b in the endometrial tissue of endometriosis patients.[15] It is known that miR-135a functions as a tumor suppressor in endometriosis and ovarian cancer by regulating HOXA10 expression, though the discrepancy between its serum and endometrial expression levels has yet to be explained.[16]

 Migration and Invasion



A study by Ohlsson Teague et al. compared paired samples of eutopic and peritoneal ectopic endometrial tissue from patients with endometriosis.[17] Microarray analysis identified 22 miRNAs that were differentially expressed, including 14 that were upregulated (miR-145, miR-143, miR-99a, miR-99b, miR-126, miR-100, miR-125b, miR-150, miR-125a, miR-223, miR-194, miR-365, miR-29c, and miR-1) and eight that were downregulated (miR-200a, miR-141, miR-200b, miR-142-3p, miR-424, miR-34c, miR-20a, and miR-196b).[17] Six were confirmed by quantitative reverse transcription polymerase chain reaction (RT-PCR). Among these, miR-145 and miR-141 were the most upregulated and downregulated, respectively. Using an in-silico analysis, 673 mRNA transcripts that were putative targets of the miRNAs were also found to be differentially expressed in eutopic versus ectopic endometrial tissue. The authors hypothesized that these transcripts constitute the molecular pathways associated with endometriosis, including c-Jun, CREB-binding protein, protein kinase B, and cyclin D1 signaling.[17] The differential expression of miR-141 in endometriosis was confirmed by a more recent study in 2019, in which Zhang et al. compared the proliferation, migration, and apoptosis of paired eutopic and ectopic endometrial stromal cells (ESCs).[18] This study showed that downregulation of miR-141-3p enhanced the proliferation and migration of ectopic ESCs, as well as reduced their rate of apoptosis via targeting the expression of Kruppel-like factor 12 (KLF-12).[18] Aberrant expression of several miRNAs including both miR-145 and miR-141 has previously been reported in epithelial ovarian cancer.[19] Further research on the mechanisms of these miRNAs may provide more insight into the pathogenesis of endometriosis in relation to other gynecological diseases.

Another miRNA, miR-200b, was found to be downregulated in a study done by Ohlsson Teague et al. Notably, this result is corroborated by a number of similar studies.[20],[21],[22],[23],[24] MiRNA-200b plays a role in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT) via targeting TGFβ2, ZEB1, and ZEB2.[17] Through EMT, epithelial cells lose their polarity and cell-to-cell contacts and acquire the invasive properties of mesenchymal cells, which are thought to be the prerequisite of endometriotic lesions.[25],[26] In addition to its role in endometriosis, miR-200b has also been reported to play a role in the metastasis of ovarian cancer.[27] In a recent study by Meng et al., miR-126-5p was found to enhance the migration and invasion of endometrial cells and thus promote the occurrence of endometriosis by negatively regulating the BCAR3 gene, which is known to play a role in cell migration, invasion, and EMT.[28]

 Angiogenesis



In 2012, Jia et al. studied miRNA expression in a group of Chinese women undergoing laparoscopy for various indications.[29] Profiling of peripheral blood of women with Stage III and IV endometriosis in comparison to those without endometriosis showed a differential expression of 27 miRNAs. Among these, six (miR-17-5p, miR-20a, miR-22, miR-15b-5p, miR-21, and miR-26a) were selected for validation with RT-PCR and the expressions of plasma miR-17-5p, miR-20a, and miR-22 were found to be significantly downregulated in women with endometriosis.[29] Similar results were reported by Ramón et al. in 2011, which found the expression of miR-17-5p and miR-20a to be significantly lower in ovarian endometriomas than in eutopic endometrium from the same patient and also patients without endometriosis.[30] In the same study, vascular endothelial growth factor-A (VEGF-A) mRNA protein levels were found to be lower in ovarian endometriomas than in eutopic endometrium, while the opposite trend was observed for angiogenic inhibitor thrombospondin-1 (TSP-1). Interestingly, while Ramón et al. reported a lack of differential expression of miR-20a in peritoneal endometriotic tissue, a separate study by Lin et al. reported upregulation of miR-20a in peritoneal and ovarian endometriotic tissues.[31] This study further demonstrates that miR-20a directly targets dual-specificity phosphatase-2, which leads to prolonged activation of ERK and overexpression of angiogenic genes such as osteopontin and Cyr61.[31] Due to its controversial expression level and questionable function on angiogenic genes, further research is necessary to delineate the role of miR-20a in the pathogenesis of endometriosis. In addition to miR-17-5p and miR-20a, Ramón et al. also reported significant inverse correlations between miR-222 and VEGF-A protein levels, as well as between miR-17-5p and TSP-1 protein levels.[30] Other miRNAs related to angiogenesis were reported in a 2014 study by Braza-Boïls et al., which found lower expression of miR-449b-3p in ovarian endometriomas than in the eutopic endometrium of patients and healthy controls.[21] Comparison between diseased eutopic endometrial tissue and healthy endometrium showed lower levels of miRNAs miR-202-3p, miR-424-5p, miR-449b-3p, and miR-556-3p, as well as higher levels of VEGF-A. The authors hypothesized that the higher levels of angiogenic activity in the eutopic endometrium of patients in comparison to healthy controls may contribute to the implantation of endometrial cells at ectopic sites.[21] From these studies, it is reasonable to conclude that these miRNAs may play a role in the pathogenesis of endometriosis by affecting the expression of angiogenic factors, though further research is needed to elucidate the exact mechanism.

 Lipid Dysfunction



In addition to contributing to the pathogenesis of endometriosis, the aberrant expression of circulating miRNA may also be partially responsible for some of the systematic symptoms of endometriosis.[6] For example, it has been reported that endometriosis may cause lipid dysfunction and fat loss,[32] therefore women with endometriosis typically have a lower body mass index (BMI) than those without.[33] A 2016 study by Goetz et al. in murine models identified 26 genes that were differentially regulated in livers of mice with endometriosis, including four genes related to weight loss that were upregulated as well as two genes associated with obesity that were downregulated.[34] The study also reported the upregulation of leptin and peroxisome proliferator-activated receptor gamma (Ppar-γ), which play key roles in regulating appetite and lipid metabolism, in mice with endometriosis.[34] In 2019, Zolbin et al. conducted a similar study by transfecting primary adipocyte cells with mimics and inhibitors of miRNAs let-7b and miR-342-3p.[35] Comparison of gene expression in women with and without endometriosis showed that endometriosis altered the expression of a number of genes involved in brown adipocyte differentiation, appetite, insulin sensitivity, and fat metabolism, including CCAAT/enhancer binding protein alpha (Cebpα) and beta (Cebpβ), Ppar-γ, leptin, adiponectin, interleukin-6, and hormone-sensitive lipase. The authors concluded that altered miRNA levels may be a mechanism by which endometriotic lesions communicate with adipocyte cells, thereby altering fat metabolism and causing the clinically observed low BMI phenotype associated with endometriosis.[34]

 Conclusion



In addition to the studies mentioned in this review, numerous other global miRNA profiling studies have found a wide range of miRNAs that were differentially expressed in endometriotic tissue in comparison to healthy tissue. miR-1, -29c, -34c, -100, -141, -145, -183, -196b, -200a, -200b, -200c, -202, -365, and -375 have all been reported to be differentially expressed in endometriosis by at least three studies.[20] A number of circulating miRNAs have also been found to be dysregulated in endometriosis patients. The ones that have been reported in at least two studies include let-7a-f, miR-9, -20a, -122, -141, -145, -199a, -342, -451a, and -3613.[7] A number of functional studies are under way to delineate the roles of these miRNAs in processes, such as cell proliferation, angiogenesis, extracellular matrix remodeling, inflammatory signaling, and hormonal regulation.[4] Based on the existing data, researchers have proposed several miRNAs as potential biomarkers in the diagnosis of endometriosis, including the let-7 family, miR-145, and miR-199a.[4],[36],[37] Although the differential expression of these miRNAs in endometriotic conditions and thus their potential in the diagnosis in the endometriosis have already been demonstrated, further research is needed in order to clarify the gene targets of these miRNAs as well as their therapeutic applications.

The studies described in this review have several common limitations. This review covered studies analyzing both endometrial miRNA from endometrial tissue samples and circulating miRNA from serum. However, there may be a discrepancy between the levels of miRNA in different types of biological samples.[2] Another factor to consider is limited sample size. The study by Burney et al., for example, had experimental and control groups of n = 4 and 3, respectively.[7] In addition to the limited number of study participants, several of the studies only included patients with advanced stage of endometriosis.[7],[12],[13],[29] Therefore, their study results may not be applicable to all stages of endometriosis. Furthermore, in studies by Cho et al. and Jia et al., although the control group individuals were not diagnosed with endometriosis, they also underwent laparoscopy for conditions such as nonendometriotic cysts, which may have affected the serum miRNA profiles.[13],[29]

Despite these limitations, these studies provide a solid starting point to understand the role of miRNAs in endometriosis. As more evidence is obtained regarding the differential expression of miRNAs in endometriotic conditions, additional functional studies are needed to confirm the specific targets of these miRNAs. Although the exact mechanism and biological functions of these miRNAs require further investigation, current research shows promising results in using miRNAs to elucidate the pathogenesis of endometriosis and as biomarkers in the noninvasive diagnosis of endometriosis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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