M2 macrophage-secreted exosomes promote metastasis and increase vascular permeability in hepatocellular carcinoma

Cell Communication and Signaling

Research

Zhi Li¹  Guoyong Han²  Zhiqiang Chen²  Qingyuan Wang²  Yiwei Lu²  Yao Zhang²  Long Zhang²  Jindao Wu³  Xuehao Wang³ 

[1] Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, China;Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation,, Nanjing Medical University Nanjing, Nanjing, Jiangsu Province, China;Department of Hepatobiliary Surgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, China;Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation,, Nanjing Medical University Nanjing, Nanjing, Jiangsu Province, China;State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China;

关键词: M2 macrophages;    Exosomes;    EMT;    Angiogenesis;    Vascular permeability;    miR-23a-3p;   

DOI  :  10.1186/s12964-022-00872-w

 received in 2022-01-17, accepted in 2022-03-31,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundMetastasis is a key feature of malignant tumors and significantly contributes to their high mortality, particularly in hepatocellular carcinoma (HCC). Therefore, it is imperative to explore the mechanism of tumor metastasis. Recently, tumor-associated macrophages (TAMs) have been demonstrated to promote tumor progression, while TAM-derived molecules involved in HCC metastasis warrant further investigation.MethodsTHP-1 was treated with IL-4 (Interleukin-4) and IL-13 (Interleukin-13) for M2 polarized macrophages. Exosomes derived from M2 macrophages were characterized. Then, HCC cells or human umbilical vein endothelial cells (HUVECs) were co-cultured with M2 macrophages or treated with M2 macrophage-secreted exosomes. Next, Transwell®, Scratch assay, tube formation, and endothelial permeability assays were performed. Moreover, RT-PCR, western blotting, immunofluorescence, and ELISA were used to assess mRNA and protein expression levels. Finally, the miRNA expression profiles of exosomes derived from M2 and M0 macrophages were analyzed.ResultsM2 macrophage infiltration was correlated with metastasis and a poor prognosis in HCC patients. M2-derived exosomes were absorbed by HCC and HUVEC cells and promoted the epithelial-mesenchymal transition (EMT), vascular permeability, and angiogenesis. Notably, MiR-23a-3p levels were significantly higher in M2-derived exosomes and hnRNPA1 mediated miR-23a-3p packaging into exosomes. Phosphatase and tensin homolog (PTEN) and tight junction protein 1 (TJP1) were the targets of miR-23a-3p, as confirmed by luciferase reporter assays. Lastly, HCC cells co-cultured with M2-derived exosomes secreted more GM-CSF, VEGF, G-CSF, MCP-1, and IL-4, which in turn further recruited M2 macrophages.ConclusionsOur findings suggest that M2 macrophage-derived miR-23a-3p enhances HCC metastasis by promoting EMT and angiogenesis, as well as increasing vascular permeability.7rQrRcgVqRWt5q73M2SSUaVideo Abstract

【 授权许可】

CC BY   
© The Author(s) 2023

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