The protein 4.1R downregulates VEGFA in M2 macrophages to inhibit colon cancer metastasis

Yu Lu; Dandan Fan; Wen Wang; Xian Gao; Hanhan Li; Shuangshuang Guo; Luyang Zhao; Yaxin Guo; Bowen Li; Yali Zhong; Binglei Zhang; Jingjing Liu; Liping Dai; Qiaozhen Kang; Zhenyu Ji

doi:10.1016/j.yexcr.2021.112896

The protein 4.1R downregulates VEGFA in M2 macrophages to inhibit colon cancer metastasis

Exp Cell Res. 2021 Dec 1;409(1):112896. doi: 10.1016/j.yexcr.2021.112896. Epub 2021 Oct 27.

Authors

Yu Lu¹, Dandan Fan², Wen Wang³, Xian Gao¹, Hanhan Li⁴, Shuangshuang Guo⁴, Luyang Zhao⁴, Yaxin Guo¹, Bowen Li¹, Yali Zhong⁵, Binglei Zhang¹, Jingjing Liu⁶, Liping Dai⁶, Qiaozhen Kang⁷, Zhenyu Ji⁸

Affiliations

¹ Henan Institute of Medical and Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China.
² Henan Institute of Medical and Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China; BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China; Henan Key Laboratory for Pharmacology of Liver Diseases, Zhengzhou, 450052, Henan, China.
³ School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China.
⁴ BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
⁵ Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁶ Henan Institute of Medical and Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China; BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China.
⁷ School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, Henan, China. Electronic address: qzkang@zzu.edu.cn.
⁸ Henan Institute of Medical and Pharmaceutical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, Henan, China; BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China; Henan Key Laboratory for Pharmacology of Liver Diseases, Zhengzhou, 450052, Henan, China. Electronic address: jizhenyu@zzu.edu.cn.

PMID: 34717920
DOI: 10.1016/j.yexcr.2021.112896

Abstract

M2 macrophages are crucial components of the tumour microenvironment and have been shown to be closely related to tumour progression. Co-culture with 4.1R^-/- M2 macrophages enhances the malignancy of colon cancer (CC), but the mechanism remains unclear. Here, we report that protein 4.1R knockout reduced the phagocytosis of M2 macrophages (M-CSF/IL-4-treated bone marrow cells) and promoted MC38 colon cancer cell proliferation, migration, invasion, tumour formation and epithelial-mesenchymal transition (EMT), which are regulated by M2 macrophages. Further mechanistic dissection revealed that the 4.1R knockout upregulated vascular endothelial growth factor A (VEGFA) secreted by M2 macrophages and promoted colon cancer progression by activating the PI3K/AKT signalling pathway. In summary, our present study identified that 4.1R downregulates VEGFA secretion in M2 macrophages and delays the malignant potential of colon cancer by inhibiting the PI3K/AKT signalling pathway.

Keywords: Colon cancer; M2 macrophages; PI3K/AKT; Protein 4.1R; VEGFA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Colonic Neoplasms / genetics*
Colonic Neoplasms / pathology
Down-Regulation / genetics*
Epithelial-Mesenchymal Transition / genetics
Female
Macrophage Activation
Macrophage Colony-Stimulating Factor / genetics
Macrophages / physiology*
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Microfilament Proteins / genetics*
Signal Transduction / genetics
Tumor Microenvironment / genetics
Vascular Endothelial Growth Factor A / genetics*

Substances

Epb41 protein, mouse
Microfilament Proteins
Vascular Endothelial Growth Factor A
vascular endothelial growth factor A, mouse
Macrophage Colony-Stimulating Factor