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N-Myc and STAT Interactor Is A Endometriosis Suppressor Gene

ABSTRACT: Endometriosis is an estrogen-dependent inflammatory disease. A pivotal contributor to endometriosis is the estrogen receptor beta (ERβ), which drives the condition by impeding cell death through interferon (IFN) signaling. One noteworthy component of this cascade is the N-myc and STAT Interactor (NMI), an interferon alpha (IFNα) target gene whose expression is repressed in endometriotic lesions compared to normal endometrium. This repression is particularly pronounced in stromal cells, mediated by ERβ. The results of Western blot analyses, comparing IFNα-treated and untreated cells, demonstrate that IFNα treatment triggers cell death signaling, including apoptosis and necroptosis, in endometrial stromal cells. Intriguingly, NMI knockdown (KD) obstructed IFNα-induced cell death signaling in human endometrial stromal cells. Moreover, NMI KD amplified non-canonical IFNα pathways, such as β-Catenin/GSK3β and PI3K/AKT signaling, in endometrial stromal cells following IFNα treatment. RNA sequencing analyses unveiled that NMI KD augmented the expression of genes responsible for cell-cell adhesion and extracellular structural organization in IFNα-independent manners. These findings suggest that NMI KD plays an indispensable role in enhancing the adhesion and invasion of endometriotic cells during endometriosis progression. In summary, NMI functions as an endometriosis suppressor gene in endometriotic stromal cells, curbing the advancement of endometriosis. This intricate interplay of ERβ, IFNα signaling, and NMI offers novel insights into the mechanisms governing endometriosis development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241751 | GEO | 2025/08/31

REPOSITORIES: GEO

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Project description:Background Reduced endometrial receptivity is a major factor for impaired fertility in endometriosis (EMS). Endometrial deposition of collagen I proteins may account for poor endometrial receptivity in endometriosis. Methods We investigated the expression of collagen I expression in endometrium of endometriosis patients and in constructed EMS mice model. Effect of collagen I on ESCs was evaluated. Co-culture of exosomes with ESCs was conducted to evaluate the uptake of exosomes by different endometrial cell lines and the effect on decidualization of eutopic ESCs and embryo implantation. MiRNA expression profiles were compared between ectopic ESC derived exosomes and eutopic ESC derived exosomes. Luciferase reporter and its mutant plasmids were applied to confirm the direct target of miR-25-3p. Findings Here we found endometrial collagen I deposition with impaired decidualization in endometriosis patients and EMS mice model. Treatment of collagen I with ESCs contributed to impaired decidualization and inhibited BLS expansion in vitro. Endometriotic stromal cell-derived exosomes were detected in eutopic endometrium and the ectopic endometrial stromal cell derived exosomes were more taken-up by the same cell line in eutopic endometrium. Treatment of endometriotic stromal cell-derived exosomes increased the expression of endometrial collagen I in vitro and in vivo, while inhibited BLS expansion. Exosomal miR-25-3p was significantly increased in endometriotic stromal cell-derived exosomes compared with control group, and PTEN is a certain target of miR-25-3p. The promotion of endometrial miR-25-3p significantly increased collagen I expression in vitro through the PTEN/Akt pathway. Interpretation These results suggested that endometriotic stromal cell-derived exosomal miR-25-3p played key role in inducing endometrial collagen I deposition to impair embryo expansion in endometriosis via PTEN/Akt pathway. Funding National Nature Science Foundation of China (82271702), National Natural Science Foundation of China (81771537). Keywords: endometriosis; exosome; collagen I; miRNA; collagen deposition

Project description:Endometriosis is a debilitating gynecological disorder affecting approximately 10% of the female population. Despite its prevalence, robust methods to classify and treat endometriosis remain elusive. Changes throughout the menstrual cycle in tissue size, architecture, cellular composition, and individual cell phenotypes make it extraordinarily challenging to identify markers or cell types associated with uterine pathologies since disease-state alterations in gene and protein expression are convoluted with cycle phase variations. Here, we developed an integrated workflow to generate both proteomic and single-cell RNA-sequencing (scRNA-seq) data sets using tissues and cells isolated from the uteri of control and endometriotic donors. Using a linear mixed effect model (LMM), we identified proteins associated with cycle stage and disease, revealing a set of genes that drive separation across these two biological variables. Further, we analyzed our scRNA-seq data to identify cell types expressing cycle and disease- associated genes identified in our proteomic data. A module scoring approach was used to identify cell types driving the enrichment of certain biological pathways, revealing several pathways of interest across different cell subpopulations. Finally, we identified ligand-receptor pairs including Axl/Tyro3 – Gas6, that may modulate interactions between endometrial macrophages and/or endometrial stromal/epithelial cells. Analysis of these signaling pathways in an independent cohort of endometrial biopsies revealed a significant decrease in Tyro3 expression in patients with endometriosis compared to controls, both transcriptionally and through histological staining. This measured decrease in Tryo3 in patients with disease could serve as a novel diagnostic biomarker or treatment avenue for patients with endometriosis. Taken together, this integrated approach provides a framework for integrating LMMs, proteomic and RNA-seq data to deconvolve the complexities of complex uterine diseases and identify novel genes and pathways underlying endometriosis.

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N-Myc and STAT Interactor Is A Endometriosis Suppressor Gene

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