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P4HA3 promotes colon cancer cell escape from macrophage phagocytosis by increasing phagocytosis immune checkpoint CD47 expression

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Abstract

Cancer immunotherapies have greatly changed the prospects for the therapy of many malignancies, including colon cancer. Macrophages as the effectors of cancer immunotherapy provide considerable promise for cancer treatment. Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) plays a cancer-promoting role in a variety of cancers, including colon cancer. In the present work, we provided evidence for the first time that P4HA3 promoted colon cancer cell escape from macrophage phagocytosis, and preliminarily explored its possible molecular mechanism. Immunohistochemistry was used to detect the expression of P4HA3 in tissues. Bioinformatics methods were used to analyze the tumor public databases (including TCGA database and GEO database). Macrophage phagocytosis assay and flow cytometric analysis were used to detect the phagocytic capacity of macrophages. Western blot and qRT-PCR were used to detect the expression of related markers (such as P4HA3, CD47, CD24, IL-34, and M-CSF). First, we found that P4HA3 was significantly and highly expressed in both colon cancer tissues and cells, and that P4HA3 had a positive correlation with lymph node metastasis, Dukes stage and also strongly correlated with poorer survival. Subsequently, we found that P4HA3 was strongly associated with the macrophage infiltration level in colon cancer. Immediately we also found that decreasing P4HA3 expression promoted macrophage phagocytosis in colon cancer cells, whereas P4HA3 overexpression produced the opposite effect. Finally, we demonstrated that P4HA3 promoted the expression of cluster of differentiation 47 (CD47) in colon cancer cells. Moreover, P4HA3 caused colon cancer cells to secrete Interleukin 34 (IL34) and Macrophage colony stimulating factor (M-CSF), which further induced macrophages to differentiate to M2 type and thereby contributed to the progression of colon cancer. We have demonstrated that P4HA3-driven CD47 overexpression may act as an escape mechanism, causing colon cancer cells to evade phagocytosis from macrophages.

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Upon reasonable request, datasets generated and/or analyzed in the course of this study may be obtained from the corresponding author.

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Funding

This study was supported by Young Science and Technology Talent Support Project of Jiangsu Association for Science and Technology (TJ-2022-063), Natural Science and Research Plan of Huai’an City (HABZ202214), Medical Education Integration Research Special Fund in Jiangsu College of Nursing (YJRH202303), Open Subjects of Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases (202204).

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  1. Hailang Zhou and Junwei Zou have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology, Lianshui People’s Hospital Affiliated to Kangda College of Nanjing Medical University, Huaian, 223400, Jiangsu, People’s Republic of China

    Hailang Zhou, Jingli Han, Aijun Zhou & Shu Huang

  2. The Institute of Life Sciences, Jiangsu College of Nursing, Huaian, 223300, Jiangsu, People’s Republic of China

    Hailang Zhou

  3. Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, Anhui, People’s Republic of China

    Junwei Zou

  4. Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, School of Clinical Medicine, Medical College of Yangzhou University, Yangzhou, 225001, Jiangsu, People’s Republic of China

    Aijun Zhou

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  1. Hailang Zhou
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Contributions

The experimental plan and protocol were conceived and designed by HZ, SH and AZ. Cellular molecular experiments are mainly completed by HZ and JZ. HZ and JZ have the equal contribution to this study. The other authors were mainly involved in data collection and data processing.

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Correspondence to Aijun Zhou or Shu Huang.

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The Ethics Committee of Lianshui People’s Hospital, affiliated with Kangda College of Nanjing Medical University, examined and approved all experiments of this study.

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Zhou, H., Zou, J., Han, J. et al. P4HA3 promotes colon cancer cell escape from macrophage phagocytosis by increasing phagocytosis immune checkpoint CD47 expression. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04927-z

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