Neutrophil extracellular traps promote growth of lung adenocarcinoma by mediating the stability of m6A-mediated SLC2A3 mRNA-induced ferroptosis resistance and CD8(+) T cell inhibition

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-01-26 DOI:10.1002/ctm2.70192

Li Xu, Yi Kong, Kang Li, Jia Li, Fang Xu, Yan Xu, Shuzhi Liang, Bolin Chen

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Abstract

To investigate the potential mechanisms underlying neutrophil extracellular traps (NETs) confer ferroptosis resistance and CD8(+) T cell inhibition in lung adenocarcinoma (LUAD). By the intravenous injection of LLC cells into the tail vein, a LUAD mouse model was created. Phorbol-12-myristate-13-acetate (PMA) stimulated neutrophils to facilitate NETs formation and combined with NETs inhibitor DNase I to explore NETs mechanism on LLC cell proliferation, migration, ferroptosis resistance, and CD8(+) T cell activity. CitH3, myeloperoxidase (MPO), cell-free DNA, and MPO-DNA levels in LUAD were increased, indicating an increase in NETs formation in LUAD. PMA promoted NETs formation in tumours of mice, increased the number of CD3(+)CD4(+) T cells, decreased perforin, granzyme A, granzyme B, IFNγ, and TNF-α levels, and promoted LUAD growth and the number of lung tumour nodules, indicating that PMA promoted NETs formation, reduced the activity of CD8(+)T cells, and promoted LUAD growth. DNase I partially reversed the effects of PMA. NETs promoted LLC cell proliferation and migration, while DNase I reversed NETs effects. Erastin inhibited LLC cell proliferation and migration and promoted ferroptosis. NETs partially reversed Erastin effects. Further results showed that NETs promoted LLC cell proliferation and migration and inhibited ferroptosis by promoting YTHDF2-mediated SLC2A3 mRNA degradation. Sh-YTHDF2 partially reversed the effect of NETs on LLC cells, whereas si-SLC2A3 partially reversed sh-YTHDF2 effects on LLC cells. In addition, NETs inhibited LLC cell ferroptosis by inhibiting CD8(+) T cell activity. Sh-YTHDF2 and DNase I inhibited NETs formation in tumours, increased the activity of CD8(+) T cells and inhibited LUAD growth. Our results suggested that NETs promoted the growth of LUAD through inhibiting ferroptosis and CD8(+) T cell activity by promoting YTHDF2-mediated SLC2A3 mRNA degradation.

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目的：研究中性粒细胞胞外捕获物（NET）赋予肺腺癌（LUAD）抗铁蛋白沉积和CD8（+）T细胞抑制作用的潜在机制。通过向尾静脉注射LLC细胞，建立了LUAD小鼠模型。光稳定剂-12-肉豆蔻酸-13-醋酸酯（PMA）刺激中性粒细胞以促进NETs的形成，并结合NETs抑制剂DNase I来探讨NETs对LLC细胞增殖、迁移、抗铁锈色素沉着和CD8（+）T细胞活性的影响机制。LUAD中CitH3、髓过氧化物酶（MPO）、细胞游离DNA和MPO-DNA水平升高，表明LUAD中NETs形成增加。PMA 促进了小鼠肿瘤中 NETs 的形成，增加了 CD3(+)CD4(+) T 细胞的数量，降低了穿孔素、颗粒酶 A、颗粒酶 B、IFNγ 和 TNF-α 的水平，促进了 LUAD 的生长和肺肿瘤结节的数量，表明 PMA 促进了 NETs 的形成，降低了 CD8(+)T 细胞的活性，促进了 LUAD 的生长。DNase I能部分逆转PMA的影响。NETs促进了LLC细胞的增殖和迁移，而DNase I则逆转了NETs的作用。Erastin抑制LLC细胞的增殖和迁移，并促进铁突变。NETs 可部分逆转 Erastin 的作用。进一步的结果显示，NETs通过促进YTHDF2介导的SLC2A3 mRNA降解，促进了LLC细胞的增殖和迁移，抑制了铁凋亡。Sh-YTHDF2部分逆转了NETs对LLC细胞的影响，而si-SLC2A3部分逆转了sh-YTHDF2对LLC细胞的影响。此外，NETs还通过抑制CD8（+）T细胞的活性来抑制LLC细胞的铁突变。Sh-YTHDF2和DNase I抑制了肿瘤中NETs的形成，提高了CD8（+）T细胞的活性，抑制了LUAD的生长。我们的研究结果表明，NETs通过抑制铁突变和CD8（+）T细胞活性，促进YTHDF2介导的SLC2A3 mRNA降解，从而促进LUAD的生长。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.