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

BackgroundBreast 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-1 alpha 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-1 alpha inhibitor PX-478 may provide a therapeutic target for BC. 1. HIF-1 alpha serves as an upstream effector to enhance circ-0100519 transcription.2. Exosomal circ-0100519, secreted from cancer cells, can be engulfed by macrophages, thereby suppressing NRF2 ubiquitination via interacting with USP7 and NRF2.3. The circ-0100519/USP7/NRF2 axis promotes the progression of breast cancer through regulating M2 macrophage polarisation. image