Process Of Endometriosis Research Articles

Wenshen Xiaozheng Tang alleviates fibrosis in endometriosis by regulating differentiation and paracrine signaling of endometrium-derived mesenchymal stem cells

Ethnopharmacological relevanceWenshen Xiaozheng Tang (WXT), a traditional Chinese medicine (TCM) decoction, is effective for treating endometriosis. However, the effect of WXT on endometrium-derived mesenchymal stem cells (eMSCs) which play a key role in the fibrogenesis of endometriosis requires further elucidation. Aims of the studyThe aim of this study was to clarify the potential mechanism of WXT in improving fibrosis in endometriosis by investigating the regulation of WXT on differentiation and paracrine of eMSCs. Materials and methodsThe nude mice with endometriosis were randomly divided into model group, WXT group and mifepristone group. After 21 days of treatment, the lesion volume was calculated. Fibrosis in the lesions was evaluated by Masson staining and expression of fibrotic proteins. The differentiation of eMSCs in vivo was explored using a fate-tracking experiment. To further clarify the regulation of WXT on eMSCs, primary eMSCs from the ectopic lesions of endometriosis patients were isolated and characterized. The effect of WXT on the proliferation and differentiation of ectopic eMSCs was examined. To evaluate the role of WXT on the paracrine activity of ectopic eMSCs, the conditioned medium (CM) from ectopic eMSCs pretreated with WXT was collected and applied to treat ectopic endometrial stromal cells (ESCs), after which the expression of fibrotic proteins in ectopic ESCs was assessed. In addition, transcriptome sequencing was used to investigate the regulatory mechanism of WXT on ectopic eMSCs, and western blot and ELISA were employed to determine the key mediator. ResultsWXT impeded the growth of ectopic lesions in nude mice with endometriosis and reduced collagen deposition and the expression of fibrotic proteins fibronectin, collagen I, α-SMA and CTGF in the endometriotic lesions. The fate-tracking experiment showed that WXT prevented human eMSCs from differentiating into myofibroblasts in the nude mice. We successfully isolated eMSCs from the lesions of patients with endometriosis and demonstrated that WXT suppressed proliferation and myofibroblast differentiation of ectopic eMSCs. Moreover, the expression of α-SMA, collagen I, fibronectin and CTGF in ectopic ESCs was significantly down-regulated by the CM of ectopic MSCs pretreated with WXT. Combining the results of RNA sequencing, western blot and ELISA, we found that WXT not only reduced thrombospondin 4 expression in ectopic eMSCs, but also decreased thrombospondin 4 secretion from ectopic eMSCs. Thrombospondin 4 concentration-dependently upregulated the expression of collagen I, fibronectin, α-SMA and CTGF in ectopic ESCs, indicating that thrombospondin 4 was a key mediator of WXT in inhibiting the fibrotic process in endometriosis. ConclusionWXT improved fibrosis in endometriosis by regulating differentiation and paracrine signaling of eMSCs. Thrombospondin 4, whose release from ectopic eMSCs is inhibited by WXT, may be a potential target for the treatment of endometriosis.

Multi-omics integration highlights the role of ubiquitination in endometriosis fibrosis

BackgroundEndometriosis, characterized by the presence of active endometrial-like tissues outside the uterus, causes symptoms like dysmenorrhea and infertility due to the fibrosis of endometrial cells, which involves excessive deposition of extracellular matrix (ECM) proteins. Ubiquitination, an important post-transcriptional modification, regulates various biological processes in human diseases. However, its role in the fibrosis process in endometriosis remains unclear.MethodsWe employed multi-omics approaches on two cohorts of endometriosis patients with 39 samples. GO terms and KEGG pathways enrichment analyses were used to investigate the functional changes involved in endometriosis. Pearson’s correlation coefficient analysis was conducted to explore the relationship between global proteome and ubiquitylome in endometriosis. The protein expression levels of ubiquitin-, fibrosis-related proteins, and E3 ubiquitin-protein ligase TRIM33 were validated via Western blot. Transfecting human endometrial stroma cells (hESCs) with TRIM33 small interfering RNA (siRNA) in vitro to explore how TRIM33 affects fibrosis-related proteins.ResultsIntegration of proteomics and transcriptomics showed genes with concurrent change of both mRNA and protein level which involved in ECM production in ectopic endometria. Ubiquitylomics distinguished 1647 and 1698 ubiquitinated lysine sites in the ectopic (EC) group compared to the normal (NC) and eutopic (EU) groups, respectively. Further multi-omics integration highlighted the essential role of ubiquitination in key fibrosis regulators in endometriosis. Correlation analysis between proteome and ubiquitylome showed correlation coefficients of 0.32 and 0.36 for ubiquitinated fibrosis proteins in EC/NC and EC/EU groups, respectively, indicating positive regulation of fibrosis-related protein expression by ubiquitination in ectopic lesions. We identified ubiquitination in 41 pivotal proteins within the fibrosis-related pathway of endometriosis. Finally, the elevated expression of TGFBR1/α-SMA/FAP/FN1/Collagen1 proteins in EC tissues were validated across independent samples. More importantly, we demonstrated that both the mRNA and protein levels of TRIM33 were reduced in endometriotic tissues. Knockdown of TRIM33 promoted TGFBR1/p-SMAD2/α-SMA/FN1 protein expressions in hESCs but did not significantly affect Collagen1/FAP levels, suggesting its inhibitory effect on fibrosis in vitro.ConclusionsThis study, employing multi-omics approaches, provides novel insights into endometriosis ubiquitination profiles and reveals aberrant expression of the E3 ubiquitin ligase TRIM33 in endometriotic tissues, emphasizing their critical involvement in fibrosis pathogenesis and potential therapeutic targets.

Identification of urine biomarkers of endometriosis-Protein mass spectrometry.

Endometriosis is a chronic inflammatory disease that leads to a series of pathological reactions. The basis is a changed proinflammatory activated immune system, which results in more pronounced oxidative stress, disturbed function of proteolysis and cell apoptosis. These processes are crucial in the development of the disease because their dysfunctional activities cause the progression of the disease. It is believed that the proteins excreted in the urine interact with each other and promote pathological processes in endometriosis. We analyzed the urine proteome of patients and aimed to detect a potential protein biomarker for endometriosis in the urine proteome. We collected urine samples from 16 patients with endometriosis and 16 patients in the control group with functional ovarian cysts. The diagnosis for all patients was confirmed through pathohistological analysis. After the preanalytical preparation of the urine, chromatography and mass spectrometry (LC-MS/MS) used the technology of urine proteome analysis. The main finding was a significantly different concentration of 14 proteins in the urine samples. We recorded a considerably higher concentration of proteins that have a significant role in activating the immune system (SELL), iron metabolism (HAMP) and cell apoptosis (CHGA) in endometriosis compared to controls. Proteins having an antioxidant function (SOD1) and a role in proteolysis of the extracellular matrix (MMP-9) were significantly reduced in endometriosis compared to controls. Consistent with the known pathogenesis of endometriosis, the study results complement the pathological responses that occur with disease progression.

Harnessing the inflammatory processes in endometriosis.

Harnessing the inflammatory processes in endometriosis.

The role of anti-Mullerian hormone in the context of modern pathogenetic approaches to the treatment of endometriosis (literature review)

Anti-Mullerian hormone (AMH) is well known as one of the key factors in reproductive development and the formation of sexual characteristics in the embryonic period in both sexes. In women, AMH is produced by granulosa cells of the preantral and early antral follicles of the ovaries and is a key biochemical marker of ovarian reserve. Recently, the role of AMH and its transmembrane receptor AMHRII as possible pathogenetic links in a number of gynecological diseases has been actively studied. The ability of AMH to cause regression of the Müllerian duct in male embryos suggests its inhibitory role for a number of benign and malignant gynecological tumors, as well as endometriosis. In this connection, active scientific research in this direction is currently underway. A number of studies have shown that AMH causes apoptosis of human endometrial stromal cells and endometriosis cells in vitro, and is also involved in the development of autophagy processes in endometriosis. The above studies demonstrate the important role of AMH in cell apoptosis in endometriosis, and indicate its therapeutic potential for a wide range of gynecological diseases. It is important to note that AMH, as a representativemember of the TGF-β superfamily, has high affinity and specificity for the AMHRII receptor, which. This fact makes further study of the function of AMH and AMHRII relevant both for assessing their effectinfluence on the processes of folliculogenesis, and reproductive aging processes, and for developing new targeting targeted therapy strategies therapy for a wide range of gynecological diseases, including endometriosis.

Hsa_circ_0005991 promotes epithelial-mesenchymal transition by regulating miR-30b-3p/Cdc42EP1 axis in ovary endometriosis

Endometriosis is a common gynecological disease with an enigmatic pathogenesis. This work explored the function of hsa_circ_0005991 in ovarian endometriosis. High-throughput RNA-Seq was conducted in five matched ectopic (EC) and eutopic (EU) samples. Further, several types of cell function experiments were conducted. According to bioinformatics analysis, a competing endogenous RNA network was established. It included 5 circRNAs, 13 miRNAs, and 551 mRNAs. The expression levels of hsa_circ_0005991 and Cdc42EP1 were significantly elevated, while miR-30b-3p was reduced in the EC group. Upregulation of hsa_circ_0005991 raised Cdc42EP1 levels, induced EMT, and boosted Ishikawa cell proliferation, migration, and invasion. hsa_circ_0005991 knockdown indicated the opposite effects. When co-transfected with miR-30b-3p mimics or inhibitors, these effects could be reversed, respectively. Western blot assays showed alterations of EMT markers in EC samples. hsa_circ_0005991/miR-30b-3p/Cdc42EP1 axis promotes the EMT process in endometriosis, which may offer a theoretical foundation for the mechanism exploration and therapy of this disease.

Proteins in urine – Possible biomarkers of endometriosis

In the pathogenesis of endometriosis, a number of pathological reactions occur. Proteins secreted in the urine are thought to interact with each other and stimulate the pathological processes in endometriosis. Identifying one or more proteins that are specific enough and could serve as biomarkers for endometriosis is both a challenge and a necessity that would facilitate diagnosis. The urine of patients treated in a tertiary university hospital between July 1, 2020 and June 30, 2021 was analyzed. The studied group consists of patients who were treated surgically for endometriosis and in whom the diagnosis was confirmed by pathohistological analysis. The control group consists of patients who were operated for functional ovarian cysts. Urinary proteins were analyzed by chromatography and mass spectrometry (LC-MS/MS). We identified 17 proteins in urine whose concentrations were statistically significantly different in the group with endometriosis (N = 16) compared with the control groups (N = 16). The detected proteins were classified into groups according to their function in invasion, migration and proliferation, proteolysis, immune system, cell adhesion and vascular system. For all mentioned proteins the difference in concentration is statistically significant p < 0.005. Proteins are secreted in the urine of patients with endometriosis that may be involved in the pathogenesis of the disease and are possible biomarkers for endometriosis.

Identification and Validation of Three m6A Regulators: FTO, HNRNPC, and HNRNPA2B1 as Potential Biomarkers for Endometriosis.

N6-methyladenosine is involved in numerous biological processes. However, the significance of m6A regulators in endometriosis is still unclear. We extracted three significant m6A regulators between non-endometriosis and endometriosis patients from GSE6364 and then we used the random forest model to obtain significant m6A regulators. In addition, we used the nomogram model to evaluate the prevalence of endometriosis. The predictive ability of the candidate genes was evaluated through the receiver operating characteristic curves, while the expression of candidate biomarkers was validated via Western blotting. Additionally, according to candidate genes, we identified m6A subtypes based on which functional enrichment analysis and immune infiltration were performed. Three significant m6A regulators (fat mass and obesity-associated protein, heterogeneous nuclear ribonucleoprotein A2/B1, and heterogeneous nuclear ribonucleoprotein C) were discovered. We identified three m6A subtypes, including clusterA, clusterB, and clusterC. ClusterB was demonstrated to be correlated with significantly overexpressed VEGF and notably downregulated ESR1 and PGR, which are convincing biomarkers of endometriosis. Furthermore, we discovered that patients in clusterB were associated with high levels of neutrophil infiltration, a reduced Treg/Th17 ratio, and overexpressed pyroptosis-related genes, which also indicated that clusterB was highly linked to endometriosis. In conclusion, m6A regulators are of great significance for the occurrence and process of endometriosis. The findings of our study provide novel insights into the underlying molecular mechanism of endometriosis. The novel investigation of m6A patterns and their correlation with immunity may also help to guide the clinical diagnosis, provide prognostic significance, and develop immunotherapy strategies for endometriosis patients.

Overexpression of ErbB-1 (EGFR) Protein in Eutopic Endometrium of Infertile Women with Severe Ovarian Endometriosis during the ‘Implantation Window’ of Menstrual Cycle

The strong association between endometriosis and infertility is of high clinical significance. High proliferative bias in eutopic endometrium during the secretory phase is a hallmark of endometriosis, which may result in high occurrence of implantation failure and resultant infertility in endometriosis. The ErbB family of proteins regulates the proliferation capacity in the endometrium, potentially causing endometrial hostility to the implantation process in endometriosis. However, our knowledge regarding the involvement of the ErbB family in human endometrium during the window of implantation (WOI) in endometriosis-associated infertility is scant. In the present study, the cellular profiles of immunopositive ErbBs-1 to -4 in the endometrium of endometriosis-free, infertile women (Group 1; n = 11) and in eutopic endometrium of infertile women diagnosed with stage IV ovarian endometriosis (Group 2; n = 13) during the mid-secretory phase were compared using standardized guidelines. Computer-aided standardized combinative analysis of immunoprecipitation in different compartments revealed an overexpression of ErbB-1 in the epithelial, stromal and vascular compartments, along with marginally higher ErbB-3 expression (p &lt; 0.06) in the vascular compartment and ErbB-4 expression (p &lt; 0.05) in the glandular epithelium and stroma in the endometrium during the WOI in women with primary infertility associated with stage IV ovarian endometriosis compared with disease-free endometrium of control infertile women. It appears that changes in ErbBs in the eutopic endometrium during WOI induce anomalous proliferative, inflammatory and angiogenic activities in it, which can antagonize endometrial preparation for embryo implantation in endometriosis. This knowledge appears usable in strategizing methods for the treatment of endometriosis-associated infertility, as well as preempting the oncogenic potential of endometriosis.

SIRT1 upregulation promotes epithelial-mesenchymal transition by inducing senescence escape in endometriosis

Endometrial epithelial cells carry distinct cancer-associated alterations that may be more susceptible to endometriosis. Mouse models have shown that overexpression of SIRT1 associated with oncogene activation contributes to the pathogenesis of endometriosis, but the underlying reason remains elusive. Here, we used integrated systems biology analysis and found that enrichment of endometrial stromal fibroblasts in endometriosis and their cellular abundance correlated negatively with epithelial cells in clinical specimens. Furthermore, endometrial epithelial cells were characterized by significant overexpression of SIRT1, which is involved in triggering the EMT switch by escaping damage or oncogene-induced induced senescence in clinical specimens and in vitro human cell line models. This observation supports that genetic and epigenetic incident favors endometrial epithelia cells escape from senescence and fuel EMT process in endometriosis, what could be overcome by downregulation of SIRT1.

Receptivity, autophagy, and implantation in endometriosis; does antioxidant work? An experimental study.

Implantation is a key point in pathological processes associated with infertility, especially in endometriosis. In this complex process, there is limited evidence to demonstrate the role of receptivity and autophagy. The present study aimed to evaluate LC3A/B, P62/SQSTM1, Beclin 1, and integrin expressions and receptivity and autophagy processes in endometriosis in pregnant rats with healthy endometriosis on day 6 of the process. Pregnancy was observed in all rats in the control group (8/8), while the pregnancy was 4/8 in the endometriosis group, and 6/8 in the endometriosis + ALA group. LC3A/B and P62/SQSTM1 expression increased significantly in the endometriosis + ALA group, compared with endometriosis groups (p < .05). The effect of ALA on autophagy and receptivity in endometriosis was shown for the first time. Antioxidant and anti-inflammatory treatments in endometriosis should be investigated as new treatment modalities for implantation problems. PRACTICAL APPLICATIONS: Endometriosis, the etiology of which remains unknown, is an important cause of infertility. Implantation is the key point in pathological processes associated with infertility. In this complex process, there is limited evidence to demonstrate the role of receptivity and autophagy. The present study aimed to evaluate LC3A/B, P62/SQSTM1, Beclin 1, and integrin expressions and receptivity and autophagy processes in endometriosis in pregnant rats with healthy endometriosis on day 6 of the process. Oral alpha-lipoic acid was administered to one group and the effect of this powerful antioxidant on the process was evaluated.

A systematic review of toll-like receptors in endometriosis.

The pathogen-associated molecular patterns and the danger-associated molecular patterns are possibly responsible for the activation of the inflammatory process in endometriosis through the activation of toll-like receptors (TLRs). The aim of this systematic review was to critically analyze the findings of published articles on TLRs in endometriosis. The keywords used were "endometriosis" and "toll-like" and the search was performed in Pubmed, Scielo and Lilacs databases. This study followed the PRISMA guidelines and the risk of bias of articles was conducted by Newcastle-Ottawa scale (NOS). Overall, the studies analyzed in this review point toward an increased expression of TLRs two, four and nine in women with endometriosis. Among all TLRs, TLR4 was the most cited receptor. Despite the evidence demonstrating elevated TLR levels in endometriosis, the relationship with the disease is still unclear and needs to be clarified in further studies about innate immune response.

Nuclear factor-kappa B signaling in endometriotic stromal cells is not inhibited by progesterone owing to an aberrant endoplasmic reticulum stress response: a possible role for an altered inflammatory process in endometriosis.

Endoplasmic reticulum (ER) stress serves as a key modulator of the inflammatory response by controlling nuclear factor-kappaB (NF-κB) signaling. Previous studies from our laboratory have reported an abnormal induction of ER stress linked to progesterone resistance in human endometriotic cells. Therefore, an aberrant ER stress response to progesterone might contribute to the altered inflammatory response observed in endometriotic tissues. To evaluate this hypothesis, we investigated whether ER stress is involved in regulation of NF-κB in endometrial stromal cells and whether induction of aberrant ER stress in endometriotic stromal cells affects pro-inflammatory cytokine production. We found that tunicamycin-induced ER stress inhibited NF-κB activation and pro-inflammatory cytokine (IL-6 and COX2) production in TNF-α- or IL-1β-treated normal endometrial stromal cells (NECSs). Tunicamycin increased the expression of A20 and C/EBPβ, which are negative regulators of NF-κB, and this increase inhibited NF-κB activity in NESCs incubated with TNF-α or IL-1β. Similarly, progesterone increased A20 and C/EBPβ expression through upregulation of ER stress in NESCs, resulting in inhibition of NF-κB activity and IL-6 and COX2 production. However, progesterone had no significant effects on induction of ER stress, A20 or C/EBPβ expression, NF-κB activity or IL-6 or COX2 production in ovarian endometriotic cyst stromal cells (ECSCs). In contrast, upregulation of ER stress by tunicamycin significantly reduced IL-6 and COX2 production by inhibiting NF-κB activity in ECSCs. In conclusion, our results suggest that NF-κB activity in endometriotic stromal cells was not inhibited because of an aberrant ER stress response to progesterone, resulting in an increase in pro-inflammatory cytokine production.

Immunologic factors involved in the malignant transformation of endometriosis to endometriosis-associated ovarian carcinoma.

Endometriosis is a risk factor for low-grade serous, clear cell, and endometroid ovarian carcinoma. In both endometriosis and ovarian carcinoma, immunological factors are associated with clinical outcome. Chronic inflammation in endometriosis may be linked to tumorigenesis, but exact processes contributing to endometriosis-associated ovarian carcinoma remain unknown. This review aims to describe potential immunological factors involved in the malignant transformation of endometriosis into ovarian carcinoma. PubMed and Embase were searched from inception up to October 2020 for studies comparing immunological processes in endometriosis and endometriosis-associated ovarian carcinoma. Detailed analysis of immune components in the malignant transformation of endometriosis into endometriosis-associated ovarian carcinoma is lacking. Altered levels of chemokines and cytokines as IL-6, IL-8, IL-10, and TNF-α are reported and the function, number and polarization of NK cells, dendritic cells, and monocytes differ between endometriosis and associated ovarian carcinoma compared to healthy tissue. In addition, altered inflammasome and complement systems, indicate a role for the immune system in the carcinogenesis of endometriosis. Chronic inflammation in endometriosis may potentially drive inflammation-induced carcinogenesis in endometriosis-associated ovarian carcinoma. Exact immunological pathways and cellular processes remain unknown and require more thorough investigation.

A randomized exploratory trial to assess the effects of resveratrol on VEGF and TNF-α 2 expression in endometriosis women

Resveratrol, a naturally synthesized polyphenolic compound found in some fruits, has anti neoplastic, anti-inflammatory, anti-oxidative, and anti-angiogenic properties. Angiogenesis is an important process in endometriosis which provides blood supply for implantation, proliferation and survival of endometriotic lesions. In this study, we assessed the effects of resveratrol on vascular endothelial growth factor (VEGF) and tumor necrosis factor alpha (TNF-α) expression in the eutopic endometrium of infertile patients with endometriosis within the window of implantation as a randomized exploratory trial. Subjects, who confirmed their endometriosis (stage III–IV) by a pathologist after laparoscopic surgery, were recruited to the present trial. A total of 34 patients were randomly divided into treatment (n = 17) and control (n = 17) groups, beside the routine protocol for treatment of endometriosis, they received resveratrol and placebo (400 mg) for 12–14 weeks, respectively. Endometrial tissue was collected from both groups before and after the intervention in the mid-secretory phase. Gene and protein expression levels of VEGF and TNF-α in the eutopic endometrium were assessed by Real-Time PCR and Western blotting, respectively. VEGF and TNF-α gene and protein levels in the treatment group showed significant decrease following intervention. It seems resveratrol may improve the endometrium of endometriosis patients in window of implantation period by modifying the expression of VEGF and TNF-α but further investigations are needed to reveal the potential role of this compound.

Oestrogen induces epithelial-mesenchymal transition in endometriosis via circ_0004712/miR-148a-3p sponge function.

Endometriosis is a common, chronic gynaecologic disease affecting up to 10% of women in their reproductive age and leading to pain and infertility. Oestrogen (E2)‐induced epithelial‐mesenchymal transition (EMT) process has been considered as a key factor of endometriosis development. Recently, the dysregulated circular RNAs (circRNAs) have been discovered in endometriosis tissues. However, the molecular mechanism of circRNAs on the E2‐induced EMT process in endometriosis is still unknown. Here, we demonstrated that circ_0004712 up‐regulated by E2 treatment in endometrial epithelial cells. Knock‐down the expression of circ_0004712 significantly suppressed E2‐induced cell migration activity. Meanwhile, we identified miR‐148a‐3p as a potential target miRNA of circ_0004712. Inhibited the expression of miR‐148a‐3p could recovered the effect of circ_0004712 knock‐down in E2‐treated endometrial epithelial. Furthermore, Western blot assay showed that E2 treatment could increase the expression and activity of β‐catenin, snail and N‐cadherin and reduce the expression of E‐cadherin. The expression and activity of β‐catenin pathway were recovered by circ_0004712 knock‐down or miR‐148a‐3p overexpression. Altogether, the results demonstrate that circ_0004712/miR‐148a‐3p plays an important role in E2‐induced EMT process in the development of endometriosis, and the molecular mechanism may be associated with the β‐catenin pathway. This work highlighted the importance of circRNAs in the development of endometriosis and provide a new biomarker for diagnosis and therapies.

Endometriosis and nuclear receptors.

Endometriosis is recognized as a steroid-dependent disorder; however, the precise roles of nuclear receptors (NRs) in steroid responsiveness and other signaling pathways are not well understood. Over the past several years, a number of paradigm-shifting breakthroughs have occurred in the area of NRs in endometriosis. We review and clarify new information regarding the mechanisms responsible for: (i) excessive estrogen biosynthesis, (ii) estrogen-dependent inflammation, (iii) defective differentiation due to progesterone resistance and (iv) enhanced survival due to deficient retinoid production and action in endometriosis. We emphasize the roles of the relevant NRs critical for these pathological processes in endometriosis. We conducted a comprehensive search using PubMed for human, animal and cellular studies published until 2018 in the following areas: endometriosis; the steroid and orphan NRs, estrogen receptors alpha (ESR1) and beta (ESR2), progesterone receptor (PGR), steroidogenic factor-1 (NR5A1) and chicken ovalbumin upstream promoter-transcription factor II (NR2F2); and retinoids. Four distinct abnormalities in the intracavitary endometrium and extra-uterine endometriotic tissue underlie endometriosis progression: dysregulated differentiation of endometrial mesenchymal cells, abnormal epigenetic marks, inflammation activated by excess estrogen and the development of progesterone resistance. Endometriotic stromal cells compose the bulk of the lesions and demonstrate widespread epigenetic abnormalities. Endometriotic stromal cells also display a wide range of abnormal NR expression. The orphan NRs NR5A1 and NR2F2 compete to regulate steroid-synthesizing genes in endometriotic stromal cells; NR5A1 dominance gives rise to excessive estrogen formation. Endometriotic stromal cells show an abnormally low ESR1:ESR2 ratio due to excessive levels of ESR2, which mediates an estrogen-driven inflammatory process and prostaglandin formation. These cells are also deficient in PGR, leading to progesterone resistance and defective retinoid synthesis. The pattern of NR expression, involving low ESR1 and PGR and high ESR2, is reminiscent of uterine leiomyoma stem cells. This led us to speculate that endometriotic stromal cells may display stem cell characteristics found in other uterine tissues. The biologic consequences of these abnormalities in endometriotic tissue include intense inflammation, defective differentiation and enhanced survival. Steroid- and other NR-related abnormalities exert genome-wide biologic effects via interaction with defective epigenetic programming and enhance inflammation in endometriotic stromal cells. New synthetic ligands, targeting PGR, retinoic acid receptors and ESR2, may offer novel treatment options.

Estradiol promotes EMT in endometriosis via MALAT1/miR200s sponge function.

Endometriosis is an estrogen-dependent benign gynecological disease that shares some common features of malignancy. Epithelial-mesenchymal transition (EMT) has been recognized as a core mechanism of endometriosis. MALAT1 is widely known as EMT promoter, while miR200 family members (miR200s) are considered as EMT inhibitors. Previous studies have reported that MALAT1 upregulation and miR200s downregulation are observed in endometriosis. MiR200c has been regarded as the strongest member of miR200s to interact with MALAT1. However, whether MALAT1/miR200c regulates EMT remains largely unclear. In this study, the roles of miR200s and MALAT1 in ectopic endometrium were investigated. Additionally, the effects of E2 on EMT and MALAT1/miR200s were examined in both EECs and Ishikawa cells. Notably, E2 could upregulate MALAT1 and downregulate miR200s expression levels and induce EMT in EECs and Ishikawa cells. PHTPP, an ERβ antagonist, could reverse the effect of E2. Overexpression of miR200c and knockdown of MALAT1 significantly inhibited E2-mediated EMT, suggesting that both miR200c and MALAT1 are involved in the E2-induced EMT process in endometriosis. In addition, a reciprocal inhibition was found between miR200s and MALAT1. Therefore, the role of MALAT1/miR200c in EMT is influenced by the presence of estrogen during endometriosis development.

Epigenetic regulation of the pathological process in endometriosis.

BackgroundEndometriosis is one of the most common gynecological diseases that greatly compromises the quality of life in affected individuals. A growing body of evidence shows that the remodeling of retrograde endometrial tissues to the ectopic endometriotic lesions involves multiple epigenetic alterations, such as DNA methylation, histone modification, and microRNA expression.MethodsThis article retrospectively reviewed the studies that were related to the epigenetic regulatory factors that contribute to the development and maintenance of endometriosis. A literature search was performed in order to collect scientific articles that were written in English by using the key words of “endometriosis,” “epigenetics,” “DNA methylation,” “histone modification,” and “microRNA.”ResultsEpigenetic modifications, including DNA methylation, histone modification, and microRNA expression, are involved in the pathogenesis of endometriosis. These epigenetic players are regulated or tuned by microenvironmental cues, such as locally produced estradiol, proinflammatory cytokines, and hypoxic stress, and reciprocally regulate the process or response to those stimuli.ConclusionUnderstanding the molecular mechanisms that underlie these epigenetic regulatory processes would shed light on the etiology and/or progression of endometriosis and facilitate the development of novel therapeutic strategies.

Epithelial-to-mesenchymal transition in the development of endometriosis.

Endometriosis, an estrogen-dependent chronic gynecological disease, is common in reproductive-age women and profoundly affects their life quality. Although various pathogenic theories have been proposed, the origin of endometriosis remains unclear. Epithelial to mesenchymal transition (EMT) is a process that epithelial cells lose polarized organization of the cytoskeleton and cell-to-cell contacts, acquiring the high motility of mesenchymal cells. These changes are thought to be prerequisites for the original establishment of endometriotic lesions. However, no study exactly indicates which type of EMT occurs in endometriosis. In this review, we conclude that two different types of EMT may participate in this disease. Besides, two stimulating signals, hypoxia and estrogen, can through different pathways to activate the EMT process in endometriosis. Those pathways involve many cellular factors such as TGF-beta and Wnt, ultimately leading to cell proliferation and migration. As infertility is becoming a serious and intractable issue for women, EMT, during the implantation process, is gaining attention. In this review, we will describe the known functions of EMT in endometriosis, and suggest further studies that may aid in the development of medical therapy.