在巨噬细胞和雌二醇的诱导下,子宫内膜基质细胞中烟酰胺 N-甲基转移酶过度表达,导致子宫内膜异位症细胞增殖。

IF 6.1 2区 生物学 Q1 CELL BIOLOGY Cell Death Discovery Pub Date : 2024-11-03 DOI:10.1038/s41420-024-02229-3
Shuhui Hou, Hui Xu, Shating Lei, Dong Zhao
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引用次数: 0

摘要

子宫内膜异位症是一种依赖雌激素的慢性炎症,困扰着育龄妇女。然而,其潜在的病理机制仍有待阐明。烟酰胺 N-甲基转移酶(NNMT)是一种参与细胞代谢和甲基化调节的关键酶。本研究调查了 NNMT 在子宫内膜异位症中的作用。通过分析数据集 GSE5108、GSE7305、GSE141549、GSE23339 和 GSE25628,我们发现与正常子宫内膜相比,NNMT 在子宫内膜异位症患者的异位内膜和异位病灶中显著过表达。此外,与各自的对照组相比,NNMT在收集的子宫内膜异位症标本和分离的原代子宫内膜基质细胞(ESC)中上调。使用 JBSNF-000088 抑制 NNMT 可减轻 ESCs 的增殖、迁移和侵袭。在体内,用 JBSNF-000088 治疗子宫内膜异位症小鼠模型可明显减轻病变的重量和数量。在 1 nM、10 nM 和 100 nM 的浓度下,17β-雌二醇会剂量依赖性地上调 ESC 中 NNMT 的表达,而 10 nM 的黄体酮会减弱这种效应。此外,用巨噬细胞条件培养基处理 HESCs 会在 mRNA 和蛋白质水平上提高 NNMT 的表达。敲除 NNMT 会阻碍 ESC 的增殖、迁移和侵袭,与此同时,Erb-b2 受体酪氨酸激酶 4(ERBB4)、PI3K 和 AKT 的磷酸化水平也会降低。相反,过表达 ERBB4 可减轻 NNMT 敲除诱导的磷酸化 PI3K 和 AKT 的下降,并挽救 ESCs 的增殖。总之,这些结果表明,雌激素和巨噬细胞相互作用诱导的NNMT过表达会通过NNMT-ERBB4-PI3K/AKT信号通路调节ESC增殖,并促进细胞迁移和侵袭,从而导致子宫内膜异位症的发生。
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Overexpressed nicotinamide N‑methyltransferase in endometrial stromal cells induced by macrophages and estradiol contributes to cell proliferation in endometriosis.

Endometriosis, an estrogen-dependent chronic inflammatory condition, afflicts reproductive-aged women. However, the underlying pathological mechanisms remain to be elucidated. Nicotinamide N-methyltransferase (NNMT) is a critical enzyme involved in cellular metabolism and methylation regulation. This study investigated the role of NNMT in endometriosis. By analyzing datasets GSE5108, GSE7305, GSE141549, GSE23339, and GSE25628, we identified a significant overexpression of NNMT in the eutopic endometrium and ectopic lesions of endometriosis patients compared to normal endometrium. Furthermore, NNMT was upregulated in collected endometrioma specimens and isolated primary endometrial stromal cells (ESCs) compared to their respective controls. Inhibition of NNMT using JBSNF-000088 attenuated the proliferation, migration, and invasion of ESCs. In vivo, treatment of mouse models of endometriosis with JBSNF-000088 resulted in a marked reduction in lesion weight and quantity. NNMT expression in ESCs was dose-dependently upregulated by 17β-estradiol at concentrations of 1 nM, 10 nM, and 100 nM, an effect that was attenuated by 10 nM progesterone. Additionally, treating HESCs with macrophage-conditioned medium elevated NNMT expression at both mRNA and protein levels. Knockdown of NNMT impeded the proliferation, migration, and invasion of ESCs, which was paralleled by decreased phosphorylation levels of Erb-b2 receptor tyrosine kinase 4 (ERBB4), PI3K, and AKT. Conversely, overexpressing ERBB4 mitigated the NNMT knockdown-induced decline in phosphorylated PI3K and AKT and rescued the proliferation of ESCs. Altogether, these results indicate that the overexpression of NNMT induced by estrogen and macrophage interaction modulates ESC proliferation via the NNMT-ERBB4-PI3K/AKT signaling pathway, as well as promotes cellular migration and invasion, contributing to the development of endometriosis.

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来源期刊
Cell Death Discovery
Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
8.30
自引率
1.40%
发文量
468
审稿时长
9 weeks
期刊介绍: Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
期刊最新文献
Correction: The possible involvement of circRNA DMNT1/p53/JAK/STAT in gestational diabetes mellitus and preeclampsia. Overexpressed nicotinamide N‑methyltransferase in endometrial stromal cells induced by macrophages and estradiol contributes to cell proliferation in endometriosis. Targeting the HECTD3-p62 axis increases the radiosensitivity of triple negative breast cancer cells. Lipids associated with autophagy: mechanisms and therapeutic targets. Myocardial ischemia-reperfusion injury upregulates nucleostemin expression via HIF-1α and c-Jun pathways and alleviates apoptosis by promoting autophagy.
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