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Nucleophosmin/B23 promotes endometrial cancer cell escape from macrophage phagocytosis by increasing CD24 expression

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Abstract

Despite recent therapeutic breakthroughs, advanced and/or recurrent endometrial cancer still poses a significant health burden globally. While immunotherapy can theoretically lead to durable responses, the benefits to patients remain limited. In an effort to identify novel immunotherapeutic targets, we specifically focused on the potential role of nucleophosmin (NPM, also known as B23) — a nucleolar phosphoprotein involved in tumorigenesis — in cancer immune evasion. Expression profiling with oligonucleotide microarrays was conducted to identify differentially expressed genes in NPM/B23-silenced endometrial cancer cells. CD24 — a heat-stable antigen commonly overexpressed in solid tumors and a target for cancer immunotherapy — was identified as one of the key NPM/B23-regulated molecules. We found that NPM/B23 was capable of inducing CD24 expression, with the Sp1 binding site in the CD24 promoter being essential for NPM/B23-mediated transcriptional activation. Interestingly, NPM/B23 silencing in endometrial cancer cells enhanced phagocytic removal by macrophages through a decreased exposure of CD24 on the cell surface. Conversely, restoration of CD24 expression in NPM/B23-silenced endometrial cancer cells inhibited macrophage-mediated phagocytosis. These results indicate that NPM/B23-driven CD24 overexpression enables endometrial cancer cells to evade from phagocytosis. We further suggest that CD24 may serve as a novel target for endometrial cancer immunotherapy.

Key messages

  • NPM/B23 induced CD24 expression in endometrial tumorigenesis.

  • Sp1 binding site in the CD24 promoter is essential for the activation.

  • NPM/B23 silencing enhanced phagocytosis by macrophages through decrease of CD24 on cancer cells.

  • Restoration of CD24 expression in NPM/B23-silenced cancer cells inhibited macrophage-mediated phagocytosis.

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Acknowledgements

We thank Jung-Erh Yang and Chu-Chun Huang for their excellent technical assistance. Formalin-fixed paraffin-embedded specimens were kindly provided by the Tumor Bank.

Funding

This study was financially supported by grants from the Chang Gung Foundation (CMRPG3K1781) and the National Science Council (NSC 107-2320-B-182A-012).

Author information

Author notes

  1. Chiao-Yun Lin and Chia-Lung Tsai contributed equally to this work.

Authors and Affiliations

  1. Gynecologic Cancer Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chiao-Yun Lin, Angel Chao, Wei-Chun Chen, Yun-Hsin Tang & Chyong-Huey Lai

  2. Department of Obstetrics and Gynecology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chiao-Yun Lin, Angel Chao, Wei-Chun Chen, Yun-Hsin Tang, An-Shine Chao & Chyong-Huey Lai

  3. Chang Gung University College of Medicine, Taoyuan, Taiwan

    Chiao-Yun Lin, Angel Chao, Wei-Chun Chen, Yun-Hsin Tang, An-Shine Chao & Chyong-Huey Lai

  4. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Chia-Lung Tsai

  5. Department of Pathology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan

    Li-Yu Lee

  6. Department of Obstetrics and Gynecology, New Taipei Municipal Tu Cheng Hospital, New Taipei City, Taiwan

    An-Shine Chao

Authors
  1. Chiao-Yun Lin
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Contributions

Conceptualization: Chiao-Yun Lin, An-Shine Chao, Chyong-Huey Lai; Methodology: Chiao-Yun Lin, Chia-Lung Tsai; Formal analysis and investigation: Chiao-Yun Lin, Angel Chao, Li-Yu Lee, Wei-Chun Chen, Yun-Hsin Tang; Writing — original draft preparation: Chiao-Yun Lin, Chia-Lung Tsai, Angel Chao; Writing — review and editing: An-Shine Chao, Chyong-Huey Lai; Funding acquisition: Chiao-Yun Lin; Resources: Angel Chao, Chyong-Huey Lai; Supervision: An-Shine Chao, Chyong-Huey Lai.

Corresponding authors

Correspondence to An-Shine Chao or Chyong-Huey Lai.

Ethics declarations

Ethics approval

Ethics approval for retrieving of clinical data from the databank of the Division of Gynecologic Oncology (Chang Gung Memorial Hospital) was granted by the local institutional review board (approval numbers: 201801840B0 and 201901344B0).

All animal procedures were approved by the Animal Care Committee of the Chang Gung Memorial Hospital Institutional Review Board (approval numbers: 2018110702 and 2019090301).

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The IRB reviewed and determined that it is expedited review according to case research or cases treated or diagnosed by clinical routines.

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The authors declare no competing interests.

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Lin, CY., Tsai, CL., Chao, A. et al. Nucleophosmin/B23 promotes endometrial cancer cell escape from macrophage phagocytosis by increasing CD24 expression. J Mol Med 99, 1125–1137 (2021). https://doi.org/10.1007/s00109-021-02079-x

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  • DOI: https://doi.org/10.1007/s00109-021-02079-x

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