ZNF746 promotes M2 macrophage polarisation and favours tumour progression in breast cancer via the Jagged1/Notch pathway

Lu Liu; Wen-Yue Zhao; Xin-Yu Zheng

doi:10.1016/j.cellsig.2023.110892

ZNF746 promotes M2 macrophage polarisation and favours tumour progression in breast cancer via the Jagged1/Notch pathway

Cell Signal. 2023 Dec:112:110892. doi: 10.1016/j.cellsig.2023.110892. Epub 2023 Sep 18.

Authors

Lu Liu¹, Wen-Yue Zhao², Xin-Yu Zheng³

Affiliations

¹ Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, China.
² Department of Thoracic Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, China.
³ Department of Breast Surgery, the First Hospital of China Medical University, Shenyang, Liaoning, China. Electronic address: xyzheng@cmu.edu.cn.

PMID: 37730102
DOI: 10.1016/j.cellsig.2023.110892

Abstract

Breast cancer (BC) is a major threat to women's health. BC is a heterogeneous disease and treatment strategies and outcomes differ between subtypes. Investigating the molecular mechanisms of BC will help to identify potential therapeutic targets and develop new therapies. Here we report that zinc finger protein 746 (ZNF746), a Krüppel-associated box and zinc finger protein, exhibits tumour-promoting properties in BC. Functional experiments (cell growth, colony formation, cell cycle analysis, and transwell analysis) were used to evaluate the proliferation, migration, and invasion capacity of BC cells. Immunohistochemistry was performed to detect the expression of ZNF746, CD163 (M2 macrophage marker), and HES1 (Notch target) in BC tissues. ZNF746 was highly expressed in BC tissues compared to adjacent paired non-tumour tissues. Patients with M1 BC had higher expression of ZNF746 compared to patients with non-metastatic (M0) BC, and higher expression of ZNF746 was associated with poorer overall survival. The immunohistochemical results showed a positive correlation between the expression of ZNF746 and the expression of CD163 or HES1. ZNF746 promoted BC cell proliferation, migration, and invasion and increased the expression of molecules essential for monocyte recruitment and differentiation (CCL2 and CSF1). Furthermore, THP-1 monocytes cultured in the conditioned medium derived from BC cells overexpressing ZNF746 exhibited enhanced M2 polarisation. In contrast, ZNF746 knockdown reduced BC cell proliferation, migration, and invasion and suppressed M2 polarisation. Mechanistically, ZNF746 promoted the activation of the Jagged1/Notch pathway, and the Jagged1 siRNA-mediated blockade of this pathway prevented the tumour-promoting functions of ZNF746. In conclusion, this study uncovers the role of ZNF746 in promoting M2 macrophage polarisation and suggests that ZNF746 may be a promising therapeutic target for limiting BC progression.

Keywords: Breast cancer; Cancer immunology; Jagged1/Notch signalling; M2 polarisation; ZNF746.

MeSH terms

Breast Neoplasms* / pathology
Cell Differentiation
Cell Line, Tumor
Female
Humans
Macrophages / metabolism
Monocytes / metabolism
RNA, Small Interfering / metabolism
Repressor Proteins / metabolism

Substances

RNA, Small Interfering
ZNF746 protein, human
Repressor Proteins