M2 macrophage-derived exosomes promote the malignant progression and glycolysis of cervical cancer via Msi1

BACKGROUND: Cervical cancer is a common gynecologic malignancy characterized by high recurrence and metastasis rate. Exosomes derived from M2-polarized tumor-associated macrophages play a key role in promoting tumorigenesis and cancer progression. Additionally, musashi1 (Msi1) is a key oncoprotein across multiple malignancies. Therefore, this study aims to determine the role of M2 macrophage-derived exosomal Msi1 in cervical cancer progression and glycolysis and to clarify the underlying mechanism. METHODS: M2 macrophages were identified using microscope, flow cytometry, and western blot. Gene mRNA and protein expression levels were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. The cell proliferation, invasion, apoptosis, and sphere formation were assessed using 5-Ethynyl-2'-deoxyuridine (EdU) staining, Transwell, flow cytometry, and sphere formation assay, respectively. The glucose uptake and lactate production were determined using commercial kits. Exosomes were identified using western blot, transmission electron microscopy, and nanoparticle tracking analysis (NTA). Cellular uptake of exosomes was assessed by incubating SiHa and Ca Ski cells with PKH67-labeled exosomes. Cervical cancer xenograft mouse models were established to analyze the role of M2 macrophage-derived exosomal Msi1. RESULTS: Msi1 expression was increased in M2 macrophages (**P < 0.01 and ***P < 0.001). Functionally, M2 macrophages enhanced cervical cancer cell proliferation, invasion, aerobic glycolysis, and stemness as well as suppressed cell apoptosis through secreting exosomes (*P < 0.05, **P < 0.01, and ***P < 0.001). Importantly, Msi1 expression was increased in M2 macrophage-derived exosomes (***P < 0.001). Mechanically, M2 macrophage-derived exosomes promoted malignancy and glycolysis by carrying Msi1 (*P < 0.01 and ***P < 0.001). In vivo, M2 macrophage-derived exosomal Msi1 accelerated cervical cancer progression (***P < 0.001). CONCLUSION: M2 macrophage-derived exosomes promote cervical cancer progression and glycolysis by delivering Msi1 to recipient cells.