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已发表论文
单细胞转录组分析揭示了 NFKB2 介导的 MIF-CD44 信号轴在子宫内膜样子宫内膜癌中的影响
Authors Zhang L, Yang M, Zhang Q, Zhang Y, Li Q, Chen Q
Received 29 April 2025
Accepted for publication 5 September 2025
Published 26 September 2025 Volume 2025:17 Pages 3293—3313
DOI https://doi.org/10.2147/IJWH.S530666
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Matteo Frigerio
Lu Zhang,1,2,* Mengjie Yang,1,2,* Quan Zhang,2 Yiqian Zhang,1,2 Qiyuan Li,2 Qionghua Chen1,2
1Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Clinical Medical Research Center for Obstetrics and Gynecology Diseases of Fujian Province, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qiyuan Li, National Institute for Data Science in Health and Medicine, Xiamen University, No. 4221-121, Xiang’an South Road, Xiang’an District, Xiamen, Fujian, People’s Republic of China, Email qiyuan.li@xmu.edu.cn Qionghua Chen, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, 24 Bailu Road, Siming District, Xiamen, Fujian, Email cqhua616@126.com
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.
Keywords: endometrial cancer, single-cell RNA sequencing, tumor microenvironment, cell communication
1Laboratory of Research and Diagnosis of Gynecological Diseases of Xiamen City, Clinical Medical Research Center for Obstetrics and Gynecology Diseases of Fujian Province, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of China; 2National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Qiyuan Li, National Institute for Data Science in Health and Medicine, Xiamen University, No. 4221-121, Xiang’an South Road, Xiang’an District, Xiamen, Fujian, People’s Republic of China, Email qiyuan.li@xmu.edu.cn Qionghua Chen, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Xiamen University, 24 Bailu Road, Siming District, Xiamen, Fujian, Email cqhua616@126.com
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.
Keywords: endometrial cancer, single-cell RNA sequencing, tumor microenvironment, cell communication