Exosomal circ‐0100519 promotes breast cancer progression via inducing M2 macrophage polarisation by USP7/NRF2 axis

Author:

Zhuang Minyu1,Zhang Xiaoqiang2,Ji Jie1,Zhang Hongfei3,Shen Li4,Zhu Yanhui1ORCID,Liu Xiaoan1

Affiliation:

1. Breast Disease Center The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu P.R. China

2. Department of Breast Surgery Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital) Hangzhou China

3. Department of Ultrasound in Medicine, Second Affiliated Hospital Zhejiang University School of Medicine Zhejiang China

4. Department of General Surgery The Fourth Affiliated Hospital of Nanjing Medical University Nanjing Medical University Nanjing Jiangsu China

Abstract

AbstractBackgroundBreast cancer (BC) is one of the most prevalent malignant tumours that threatens women health worldwide. It has been reported that circular RNAs (circRNAs) play an important role in regulating tumour progression and tumour microenvironment (TME) remodelling.MethodsDifferentially expression characteristics and immune correlations of circRNAs in BC were verified using high‐throughput sequencing and bioinformatic analysis. Exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. The biological function of circ‐0100519 in BC development was demonstrated both in vitro and in vivo. Western blotting, RNA pull‐down, RNA immunoprecipitation, flow cytometry, and luciferase reporter were conducted to investigate the underlying mechanism.ResultsCirc‐0100519 was significant abundant in BC tumour tissues and related to poor prognosis. It can be encapsulated into secreted exosomes, thereby promoting BC cell invasion and metastasis via inducing M2‐like macrophages polarisation.Mechanistically, circ‐0100519 acted as a scaffold to enhance the interaction between the deubiquitinating enzyme ubiquitin‐specific protease 7 (USP7) and nuclear factor‐like 2 (NRF2) in macrophages, inducing the USP7‐mediated deubiquitination of NRF2. Additionally, HIF‐1α could function as an upstream effector to enhance circ‐0100519 transcription.ConclusionsOur study revealed that exosomal circ‐0100519 is a potential biomarker for BC diagnosis and prognosis, and the HIF‐1α inhibitor PX‐478 may provide a therapeutic target for BC.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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