Dataset Information

The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway.

ABSTRACT: Endometrial receptivity is essential for successful pregnancy, and its impairment is a major cause of embryo-implantation failure. MicroRNAs (miRNAs) that regulate epigenetic modifications have been associated with endometrial receptivity. However, the molecular mechanisms whereby miRNAs regulate endometrial receptivity remain unclear. Therefore, we investigated whether miR-182 and its potential targets influence trophoblast cell attachment. miR-182 was expressed at lower levels in the secretory phase than in the proliferative phase of endometrium tissues from fertile donors. However, miR-182 expression was upregulated during the secretory phase in infertile women. Transfecting a synthetic miR-182-5p mimic decreased spheroid attachment of human JAr choriocarcinoma cells and E-cadherin expression (which is important for endometrial receptivity). miR-182-5p also downregulated N-Myc downstream regulated 1 (NDRG1), which was studied further. NDRG1 was upregulated in the secretory phase of the endometrium tissues and induced E-cadherin expression through the nuclear factor-κΒ (NF-κΒ)/zinc finger E-box binding homeobox 1 (ZEB1) signaling pathway. NDRG1-overexpressing or -depleted cells showed altered attachment rates of JAr spheroids. Collectively, our findings indicate that miR-182-5p-mediated NDRG1 downregulation impaired embryo implantation by upregulating the NF-κΒ/ZEB1/E-cadherin pathway. Hence, miR-182-5p is a potential biomarker for negative selection in endometrial receptivity and a therapeutic target for successful embryo implantation.

SUBMITTER: Yu SL

PROVIDER: S-EPMC9602861 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway.

Yu Seong-Lan SL Kang Yujin Y Jeong Da-Un DU Lee Dong Chul DC Jeon Hye Jin HJ Kim Tae-Hyun TH Lee Sung Ki SK Han Ae Ra AR Kang Jaeku J Park Seok-Rae SR

International journal of molecular sciences 20221014 20

Endometrial receptivity is essential for successful pregnancy, and its impairment is a major cause of embryo-implantation failure. MicroRNAs (miRNAs) that regulate epigenetic modifications have been associated with endometrial receptivity. However, the molecular mechanisms whereby miRNAs regulate endometrial receptivity remain unclear. Therefore, we investigated whether miR-182 and its potential targets influence trophoblast cell attachment. miR-182 was expressed at lower levels in the secretory ...[more]

PMID: 36293154

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Project description:BackgroundAdenomyosis is a common gynecological disease which seriously impacts female fertility and is increasing in incidence in women of childbearing age. Melatonin has beneficial effects on reproductive processes. However, its impact on the uterine receptivity of patients with adenomyosis remains unclear. In this study, we investigated the effect of melatonin on uterine receptivity and pregnancy outcomes in an adenomyosis mouse model.MethodsWe induced an adenomyosis mouse model by oral administration of tamoxifen to neonatal female CD-1 mice, then conducted a melatonin injection experiment to investigate its effect on implantation rates (n=6 each). In a second experiment, the endometrium in the implantation state was collected to identify the local action of melatonin on adenomyosis mice (n=6 each), and in a parallel study, the pregnancy rate and number of offspring were recorded (n=6 each).ResultsThe number of implantation sites in the adenomyosis model mice was much less than in control group (5.0±2.10 vs. 13.3±2.38, P<0.0001), and 30 mg/kg of melatonin significantly improved this (9.0±0.63 vs. 5.0±2.10, P=0.002). Additionally, melatonin administration ameliorated the impaired endometrial receptivity [leukemia inhibitory factor (LIF), integrin β3, homeobox A10 (HoxA10), and HoxA11], and improved the endometrium development [endometrial area (EA) and endometrial thickness index (ETI)] and pregnancy outcomes. Furthermore, the expression of implantation-related genes (Era, Pra, and P53), inflammatory factors [tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)], oxidative stress associated genes (Gpx1 and Sod1), and apoptosis-related genes or proteins (Bax, Bcl-2, caspase-3, and cleaved caspase-3) was detected. The results showed higher local levels of reactive oxygen species (ROS) and inflammatory cytokines in the uterus of an adenomyosis model mice induced endometrial cells apoptosis and tissue damage, changed the uterine microenvironment, affected embryo implantation, and reduced the fertility of adenomyosis. Interestingly, melatonin significantly mitigated adenomyosis-induced changes by inhibiting the nuclear factor kappa B (NF-κB) signaling pathway, increasing the vascular endothelial growth factor (VEGF) expression, decreasing the endometrial cells apoptosis, and improving pregnancy outcomes.ConclusionsMelatonin treatment restored impaired uterine development and endometrial receptivity of adenomyosis mice by improving the endometrial microenvironment via the NF-κB/apoptosis signaling pathway. Our results provided new insight into melatonin-based therapy for adenomyosis-related infertility.

Project description:BackgroundThe endometrial luminal epithelium is the first point of attachment of embryos during implantation. Failure of embryos to firmly adhere results in implantation failure and infertility. A receptive endometrial luminal epithelium is achieved through the expression of adhesion molecules in the mid-secretory phase and is a requirement for implantation. Cadherin 6 (CDH6) is an adhesion molecule localizing to the endometrial luminal epithelial cell surface in the mid-secretory/receptive phase and knockdown of CDH6 in the Ishikawa cells (receptive endometrial epithelial cell line) compromises cell integrity. However, there are no studies investigating the role of CDH6 on receptivity and infertility. This study aimed to investigate whether CDH6 is dysregulated in the endometrium of women with infertility during the receptive window and the effect of CDH6 on endometrial adhesion and receptivity.MethodsThe expression and the localization of CDH6 in the human endometrium were determined by immunohistochemistry. Ishikawa cells were used to investigate the functional consequences of CDH6 knockdown on endometrial adhesive capacity to HTR8/SVneo (trophoblast cell line) spheroids in vitro. CDH6 knockdown was assessed by qPCR and immunoblotting. After CDH6 knockdown, the expression of type II cadherin family members and CDH6 functional partners were assessed by qPCR. Two-tailed unpaired student's t-test or one-way ANOVA as appropriate were used for statistical analysis with a significance threshold of P < 0.05.ResultsA significant reduction of CDH6 immunolocalization was recorded in the luminal and glandular epithelium of endometrium from women with infertility (P < 0.05) compared to fertile group respective cellular compartments in the mid-secretory phase. Functional analysis using Ishikawa cells demonstrated that knockdown of CDH6 (treated with 50 nM CDH6 siRNA) significantly reduced epithelial adhesive capacity (P < 0.05) to HTR8/SVneo spheroids compared to control and other type II cadherin family members likely failed to compensate for the loss of CDH6. The expression levels of CDH6 functional partners, catenin family members were not changed after CDH6 knockdown in Ishikawa cells.ConclusionTogether, our data revealed that CDH6 was dysregulated in the endometrium from women with infertility and altered Ishikawa cell adhesive capacity. Our study supports a role for CDH6 in regulating endometrial adhesion and implantation.

Dataset Information

The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway.

Publications

The miR-182-5p/NDRG1 Axis Controls Endometrial Receptivity through the NF-κB/ZEB1/E-Cadherin Pathway.

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