Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.
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ABSTRACT:
SUBMITTER: Jeong JW
PROVIDER: S-EPMC2681319 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of GATA binding protein 2 (Gata2) are infertile, showing failures in embryo implantation, endometrial decidualization, and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR) expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of the Pgr gene but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer-related molecular profile in a progesterone-independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mice based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.
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Project description:We have developed apical-out (AO)- endometrial organoids (EMO) that emulate the in vivo archtecture of endometrial epithelium. The AO-EMO exposes the apical surface of the epithelium. To explore the hormone responsiveness and spatial heterogeneity of AO-EMO, we conducted transcriptomic analysis.
2023-11-11 | GSE239657 | GEO
Project description:Background:Estrogen receptor (ER) and progesterone receptor (PR) are involved in endometriosis, but the involvement of microRNAs (miRNAs) is unknown. The aim of the study was to explore the correlation between miRNA and ER/PR in uterine tissues of rats with endometriosis during the implantation window. Methods:Twenty female Sprague-Dawley rats were randomized in three groups: endometriosis (n = 7), fat tissue control (n = 6), and normal (n = 7) groups. The female rats were mated and sacrificed on day 5 (implantation). Uterine tissues were obtained for hematoxylin-eosin staining, immunohistochemistry, and miRNA expression. Reverse transcription polymerase chain reaction (RT-PCR) was used to validate the expression of rno-miR-29c-3p, rno-miR-34c-5p, rno-miR-141-5p, rno-miR-24-1-5p, and rno-miR-490-5p. Results:The 475 miRNAs were found to differentially express between the endometriosis and normal control groups, with 127 being upregulated and 348 being downregulated. Expression of five miRNAs (rno-miR-29c-3p, rno-miR-34c-5p, rno-miR-141-5p, rno-miR-24-1-5p, and rno-miR-490-5p) were validated by RT-PCR and found to be differentially expressed among the three groups. Expression of ER and PR proteins (immunohistochemistry) in the glandular epithelium and endometrial stroma was significantly different among the three groups (all P < 0.05). Five miRNAs were involved in pathways probably taking part in implantation and fertility. Conclusions:The results suggested that miRNAs, ER, and PR could play important roles in the embryo implantation period of rats with endometriosis. These miRNAs might play a role in endometrial receptivity in endometriosis.
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Project description:During decidualization, endometrial stromal cells differentiate into a secretory phenotype to modulate the uterine microenvironment and promote embryo implantation. This highly metabolic process relies on ovarian steroid receptors and glucose transporters. Canonical Notch signaling is mediated by the transcription factor Recombination Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ). Loss of RBPJ in the mouse uterus (Pgrcre/+Rbpjflox/flox; Rbpj c-KO) results in subfertility in part due to an abnormal uterine-embryonic axis during implantation and, as described herein, decidualization failure. Induced in vivo decidualization in Rbpj c-KO mice was impaired with the downregulation of decidual markers and decreased progesterone receptor (Pgr) signaling. Consistent with in vivo mouse data, RBPJ knockdown during in vitro Human uterine fibroblast (HuF) cell decidualization results in the reduced expression of decidual marker genes along with PGR. Expression of the glucose transporter, SLC2A1, was decreased in the RBPJ-silenced HuF cells, which corresponded to decreased Slc2a1 in the secondary decidual zone of Rbpj c-KO mouse uteri. Exogenous administration of pyruvate, which bypasses the need for glucose, rescues PRL expression in RBPJ-deficient HuF cells. In summary, Notch signaling through RBPJ controls both ovarian steroid receptor PGR and glucose transporter SLC2A1 expression during decidualization, and this dysregulation likely contributes to embryo implantation failure.
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Project description:BackgroundPremature ovarian insufficiency (POI) is a clinical syndrome resulting from loss of ovarian function before the age of 40. It is a state of hypergonadotropic hypogonadism, characterised by amenorrhoea or oligomenorrhoea, with low ovarian sex hormones (oestrogen deficiency) and elevated pituitary gonadotrophins. POI with primary amenorrhoea may occur as a result of chromosomal and genetic abnormalities, such as Turner syndrome, Fragile X, or autosomal gene defects; secondary amenorrhoea may be iatrogenic after the surgical removal of the ovaries, radiotherapy, or chemotherapy. Other causes include autoimmune diseases, viral infections, and environmental factors; in most cases, POI is idiopathic. Appropriate replacement of sex hormones in women with POI may facilitate the achievement of near normal uterine development. However, the optimal effective hormone therapy (HT) regimen to maximise the reproductive potential for women with POI remains unclear.ObjectivesTo investigate the effectiveness and safety of different hormonal regimens on uterine and endometrial development in women with POI.Search methodsWe searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two trials registers in September 2021. We also checked references of included studies, and contacted study authors to identify additional studies.Selection criteriaWe included randomised controlled trials (RCTs) investigating the effect of various hormonal preparations on the uterine development of women diagnosed with POI.Data collection and analysisWe used standard methodological procedures recommended by Cochrane. The primary review outcome was uterine volume; secondary outcomes were endometrial thickness, endometrial histology, uterine perfusion, reproductive outcomes, and any reported adverse events.Main resultsWe included three studies (52 participants analysed in total) investigating the role of various hormonal preparations in three different contexts, which deemed meta-analysis unfeasible. We found very low-certainty evidence; the main limitation was very serious imprecision due to small sample size. Conjugated oral oestrogens versus transdermal 17ß-oestradiol We are uncertain of the effect of conjugated oral oestrogens compared to transdermal 17ß-oestradiol (mean difference (MD) -18.2 (mL), 95% confidence interval (CI) -23.18 to -13.22; 1 RCT, N = 12; very low-certainty evidence) on uterine volume, measured after 12 months of treatment. The study reported no other relevant outcomes (including adverse events). Low versus high 17ß-oestradiol dose We are uncertain of the effect of a lower dose of 17ß-oestradiol compared to a higher dose of 17ß-oestradiol on uterine volume after three or five years of treatment, or adverse events (1 RCT, N = 20; very low-certainty evidence). The study reported no other relevant outcomes. Oral versus vaginal administration of oestradiol and dydrogesterone We are uncertain of the effect of an oral or vaginal administration route on uterine volume and endometrial thickness after 14 or 21 days of administration (1 RCT, N = 20; very low-certainty evidence). The study reported no other relevant outcomes (including adverse events).Authors' conclusionsNo clear conclusions can be drawn in this systematic review, due to the very low-certainty of the evidence. There is a need for pragmatic, well designed, randomised controlled trials, with adequate power to detect differences between various HT regimens on uterine growth, endometrial development, and pregnancy outcomes following the transfer of donated gametes or embryos in women diagnosed with POI.
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Project description:Pregnancy induces changes in the transcriptome of the bovine endometrium from 15 days after insemination. However, pregnancy is less likely to occur if cows had a postpartum bacterial infection of the uterus, even after the resolution of disease. We hypothesized that uterine bacterial infection alters the endometrial transcriptomic signature of pregnancy after the resolution of disease. To examine the endometrial transcriptomic signature of pregnancy, cows were inseminated 130 days after intrauterine infusion of pathogenic Escherichia coli and Trueperella pyogenes, subsequently endometrium was collected 16 days after insemination for RNA sequencing. We found 171 pregnancy regulated genes in cows 146 days after bacterial infection. When comparing our findings with previous studies that described the endometrial transcriptomic signature of pregnancy in healthy cows, 24 genes were consistently differentially expressed in pregnancy, including MX1, MX2 and STAT1. However, 12 pregnancy regulated genes were found only in the endometrium of healthy cows, including ISG15 and TRANK1. Furthermore, 28 pregnancy regulated genes were found only in the endometrium of cows following bacterial infection and these were associated with altered iNOS, TLR, and IL-7 signaling pathways. Although 94 predicted upstream regulators were conserved amongst the studies, 14 were found only in the endometrium of pregnant healthy cows, and 5 were found only in cows following bacterial infection, including AIRE, NFKBIA, and DUSP1. In conclusion, there were both consistent and discordant features of the endometrial transcriptomic signature of pregnancy 146 days after intrauterine bacterial infusion. These findings imply that there is an essential transcriptomic signature of pregnancy, but that infection induces long-term changes in the endometrium that affect the transcriptomic response to pregnancy.
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Project description:The ovarian steroid hormones, estrogen (E2) and progesterone (P4), are essential regulators of uterine biology. The imbalance of these ovarian steroid hormones leads to uterine diseases such as endometrial cancer, endometriosis, and infertility. Mitogen-inducible gene 6 (MIG-6) is an adaptor protein. MIG-6 mediates P4 signaling and acts as a tumor suppressor during endometrial tumorigenesis in both humans and mice. In previous studies, we developed the conditional knockout of Mig-6 in all uterine compartments (Pgrcre/+Mig-6f/f; Mig-6KO) and endometrial epithelial cell-specific Mig-6 knockout (Sprr2fcre/+Mig-6f/f; Mig-6Ep-KO) mice. Both mouse models developed endometrial hyperplasia and E2-dependent endometrial cancer. P4 treatment significantly decreases aberrant epithelial proliferation and AKT signaling in Mig-6Ep-KO mice but not in Mig-6KO mice. In the present study, we identified a calcium-dependent phospholipase A2 (cPla2) as one of the genes down-regulated by Mig-6 in the uterus. We performed immunohistochemistry and Western Blot analysis to investigate the regulation of cPLA2 by MIG-6 as well as determine the expression patterns of cPLA2 in the uterus. While the expression of cPLA2 was stronger at the uterine epithelial cells of Mig-6KO and Mig-6Ep-KO mice compared to control mice, P4 suppressed the expression of cPLA2 in Mig-6Ep-KO mice but not in Mig-6KO mice. To determine the ovarian steroid hormone regulation of cPLA2, we examined the expression of cPLA2 in ovariectomized control, Mig-6KO, Mig-6Ep-KO, and PRKO mice treated with P4 or E2. After P4 treatment, cPLA2 expression was remarkably reduced in Mig-6Ep-KO mice but not in Mig-6KO mice. However, the expression of cPLA2 was not changed in PRKO mice. Our results identified cPLA2 as a novel target of MIG-6 in the murine uterus and identified its important role during endometrial tumorigenesis.
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Project description:STUDY QUESTION:How does aquaporin-3 (AQP3) affect endometrial receptivity? SUMMARY ANSWER:AQP3, which is regulated by the combination and estrogen (E2) and progesterone (P4), induces epithelial-mesenchymal transition (EMT) of endometrial epithelial cells. WHAT IS KNOWN ALREADY:Embryo implantation is an extremely complex process, and endometrial receptivity is essential for successful embryo implantation. Estrogen and progesterone regulate endometrial receptivity. AQP3, which is regulated by estrogen (E2), increases cell migration and invasion ability by regulating the expression of EMT-related factors and influencing the reorganization of the actin cytoskeleton. STUDY DESIGN, SIZE, DURATION:This study investigated the pathophysiological significance of AQP3 in human endometrial function during different phases of the menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS:AQP3 expression levels during different phases of the menstrual cycle were measured using immunohistochemical assays. In cells of different receptivity (high-receptive RL95-2 cells and low-receptive HEC-1A cells), the expression of AQP3 was measured using western blotting, qRT-PCR and immunofluorescence assays. Activities of AQP3, and its regulation by E2 and P4, were studied through in-vitro experiments using RL95-2 cells. MAIN RESULTS AND THE ROLE OF CHANCE:AQP3 expression in the mid- and late-secretory phases of the human endometrium is significantly higher than in other phases. Since AQP3 expression levels were higher in RL95-2 cells than in HEC-1A cells, mechanisms of AQP3 regulation by E2 and P4 were studied using RL95-2 cells. We provided the first report that P4 up-regulates AQP3 by directly targeting the promoter of the AQP3 gene. The up-regulation of AQP3 expression by a combination of E2 and P4 is significantly higher than that caused by either E2 or P4 alone. Together E2 and P4 promote RL95-2 cell migration and invasion by inducing EMT through AQP3. We also found that AQP3 co-localizes with ezrin and affects the formation of filopodia and lamellipodia during the E2 and P4-induced EMT process but has no effect on the expression of ezrin and F-actin. LARGE SCALE DATA:N/A. LIMITATIONS, REASONS FOR CAUTION:It is still unclear whether AQP3 is a main regulator of endometrial receptivity or one of several factors influencing the process. WIDER IMPLICATIONS OF THE FINDINGS:Further investigation on AQP3 may contribute to a greater understanding of endometrial receptivity. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by the National Natural Scientific Grants of China (No. 31570798), the Program for Liaoning Excellent Talents in University (LR2017042), the Doctoral Scientific Research Foundation of Liaoning province (201601236), and the Liaoning Provincial Program for Top Discipline of Basic Medical Sciences. There are no conflicts of interest.
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Project description:Abstract Background Uterine corpus endometrial carcinoma (UCEC) ranks sixth among malignant tumors in women and the mortality is still rising. FAT2 gene has been considered to be related to the survival and prognosis of some certain diseases in previous studies, but the FAT2 mutation status in UCEC and its prognostic value has been rarely studied. Hence, the purpose of our study was to explore the role of FAT2 mutations for predicting prognosis and responsiveness to immunotherapy in patients with UCEC. Methods UCEC samples from the Cancer Genome Atlas database were analyzed. We evaluated the impact of FAT2 gene mutation status and clinicopathological characteristics on the prognosis of UCEC patients and used univariate and multivariate Cox analysis risk scores to independently predict patient overall survival (OS). Tumor mutation burden (TMB) values of the FAT2 mutant and non‐mutant groups were computed by Wilcoxon rank sum test. The correlation of FAT2 mutation and half maximal inhibitory concentration (IC50) values of various anticancer drugs was analyzed. Gene Ontology data and Gene Set Enrichment Analysis (GSEA) were employed to examine the differential expression of genes between the two groups. Finally, a single‐sample GSEA arithmetic was utilized to measure the abundance of tumor‐infiltrating immune cells in UCEC patients. Results FAT2 mutations suggested better OS (p < 0.001) and disease‐free survival (DFS) (p = 0.007) in UCEC. The IC50 values of 18 anticancer drugs were upregulated in FAT2 mutation patients (p < 0.05). The TMB and microsatellite instability values of patients with FAT2 mutations were significantly higher (p < 0.001). Next, the Kyoto Encyclopedia of Genes and Genomes functional analysis and GSEA revealed the potential mechanism of FAT2 mutation on the tumorigenesis and progression of UCEC. In addition, in reference to the UCEC microenvironment, the infiltration levels of activated CD4/CD8 T cells (p < 0.001/p = 0.001) and plasmacytoid dendritic cells (p = 0.006) were upregulated in the non‐FAT2 mutation group, and Type 2 T helper cells (p = 0.001) were downregulated in the FAT2 mutation group. Conclusions UCEC patients with FAT2 mutations have better prognosis and are more likely to respond to immunotherapy. FAT2 mutation may be a valuable predictor for prognosis and responsiveness to immunotherapy in UCEC patients. UCEC patients with FAT2 mutations have better prognosis. FAT2 mutation may be an independent prognostic predictor for UCEC.
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Project description:Uterine corpus endometrial carcinoma (UCEC) is a common malignant tumor of the female reproductive system with poor prognosis in advanced, recurrent, and metastatic cases. Identification of reliable molecular markers will help in the development of clinical strategies for early detection, diagnosis, and intervention. Gamma-glutamyl hydrolase (GGH) is a key enzyme in folate metabolism pathway. High expression of GGH is associated with severe clinicopathological features and poor prognosis of several cancers. High GGH expression is also related to cell resistance to antifolate drugs such as methotrexate. In this study we focused on the prognostic value of immunohistochemical GGH expression level in UCEC tissue and RNA-seq data from The Cancer Genome Atlas to establish associations with clinical features and outcomes. Further, we conducted comprehensive bioinformatics analyses to identify and functionally annotate differentially expressed genes (DEGs) associated with UCEC upregulation and assessed the effects of upregulation on immune infiltration. Both GGH mRNA and protein expression levels were elevated in tumor tissues, and higher expression was significantly associated with advanced clinicopathological features and poor prognosis by univariate analysis. Further multivariate analysis identified elevated GGH expression as an independent risk factor for poor outcome. Nomograms including GGH expression yielded a c-index for disease-specific survival prediction of 0.884 (95% confidence interval: 0.861-0.907). A total of 520 DEGs (111 upregulated and 409 downregulated) were identified between high and low GGH expression groups. Analysis using Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway, Gene set enrichment analysis, and protein‒protein interaction indicated significant associations of altered GGH expression with cell proliferation, immune response, and the occurrence and development of UCEC tumors. Finally, GGH expression level was associated with high Th2 cell and low natural killer CD56bright cell infiltration. Collectively, these findings indicate that GGH drives UCEC progression and could be a useful biomarker for survival prediction as well as a therapeutic target.
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