Single-Cell Transcriptomic Analysis Highlights the Impact of NFKB2-Mediated MIF-CD44 Signaling Axis in Endometrioid Endometrial Cancer.

IF 2.6 4区 医学 Q2 OBSTETRICS & GYNECOLOGY
International Journal of Women's Health Pub Date : 2025-09-26 eCollection Date: 2025-01-01 DOI:10.2147/IJWH.S530666
Lu Zhang, Mengjie Yang, Quan Zhang, Yiqian Zhang, Qiyuan Li, Qionghua Chen
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引用次数: 0

Abstract

Background: The tumor microenvironment (TME) is a complex network driving endometrioid endometrial cancer (EC) progression. Previous analyses of the EC TME were often limited by a lack of detailed cellular annotations. Integrating single-cell RNA sequencing (scRNA-seq) data offers a comprehensive approach to reconstruct the TME, aiming to uncover novel mechanisms and therapeutic targets.

Methods: We integrated public scRNA-seq data from 15 EC and 5 normal endometrium samples. Through detailed cell annotation, we performed comprehensive bioinformatic analyses, including pseudotime trajectories, copy number variation, and cell communication, to investigate mechanisms of EC development.

Results: We identified nine cell types and characterized subpopulations of epithelial, macrophage, lymphocyte, and stromal fibroblast cells. The SOX9+LGR5- epithelial subtype showed elevated malignancy and NFKB pathway enrichment. The M2_like2 macrophage subtype played a critical role, engaging in robust MIF-(CD74+CD44) mediated communication with SOX9+LGR5- cells. Experimental validation confirmed MIF co-expression with E-cadherin in EC tissues. Furthermore, the transcription factor NFKB2 was found to mediate MIF's effect on the CD44 receptor in malignant epithelial cells. A pericyte-to-fibroblast transition in stromal cells may also support tumor growth, while an increase in CD8 exhausted/Treg cells and a decrease in cytotoxic CD8 cells suggest potential immune evasion.

Conclusion: Our single-cell analysis details the EC TME landscape, revealing robust communication between M2_like2 macrophages and SOX9+LGR5- epithelial cells. We highlight a key mechanism where NFKB2 mediates MIF's pro-tumorigenic effects via the CD44 receptor, offering new insights into EC progression and potential therapeutic targets.

单细胞转录组学分析强调了nfkb2介导的MIF-CD44信号轴在子宫内膜样子宫内膜癌中的作用。
背景:肿瘤微环境(tumor microenvironment, TME)是驱动子宫内膜样子宫内膜癌(endometrioid endomecancer, EC)进展的复杂网络。以前对EC TME的分析常常受到缺乏详细细胞注释的限制。整合单细胞RNA测序(scRNA-seq)数据为重建TME提供了全面的方法,旨在揭示新的机制和治疗靶点。方法:我们整合了15例EC和5例正常子宫内膜样本的公开scRNA-seq数据。通过详细的细胞注释,我们进行了全面的生物信息学分析,包括假时间轨迹,拷贝数变化和细胞通讯,以研究EC发展的机制。结果:我们鉴定了9种细胞类型,并鉴定了上皮细胞、巨噬细胞、淋巴细胞和间质成纤维细胞亚群。SOX9+LGR5-上皮亚型显示恶性升高和NFKB通路富集。M2_like2巨噬细胞亚型发挥了关键作用,参与MIF-(CD74+CD44)介导的与SOX9+LGR5-细胞的强大通信。实验证实MIF与E-cadherin在EC组织中共表达。此外,在恶性上皮细胞中发现转录因子NFKB2介导MIF对CD44受体的影响。基质细胞中周细胞向成纤维细胞的转变也可能支持肿瘤生长,而CD8耗竭/Treg细胞的增加和细胞毒性CD8细胞的减少提示潜在的免疫逃避。结论:我们的单细胞分析详细描述了EC TME景观,揭示了M2_like2巨噬细胞与SOX9+LGR5-上皮细胞之间的强大通信。我们强调了NFKB2通过CD44受体介导MIF的促肿瘤作用的关键机制,为EC的进展和潜在的治疗靶点提供了新的见解。
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来源期刊
International Journal of Women's Health
International Journal of Women's Health OBSTETRICS & GYNECOLOGY-
CiteScore
3.70
自引率
0.00%
发文量
194
审稿时长
16 weeks
期刊介绍: International Journal of Women''s Health is an international, peer-reviewed, open access, online journal. Publishing original research, reports, editorials, reviews and commentaries on all aspects of women''s healthcare including gynecology, obstetrics, and breast cancer. Subject areas include: Chronic conditions including cancers of various organs specific and not specific to women Migraine, headaches, arthritis, osteoporosis Endocrine and autoimmune syndromes - asthma, multiple sclerosis, lupus, diabetes Sexual and reproductive health including fertility patterns and emerging technologies to address infertility Infectious disease with chronic sequelae including HIV/AIDS, HPV, PID, and other STDs Psychological and psychosocial conditions - depression across the life span, substance abuse, domestic violence Health maintenance among aging females - factors affecting the quality of life including physical, social and mental issues Avenues for health promotion and disease prevention across the life span Male vs female incidence comparisons for conditions that affect both genders.
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