M2 macrophage-derived exosomes promote cell proliferation, migration and EMT of non-small cell lung cancer by secreting miR-155-5p

Tumor-associated macrophages (TAMs) are a type of highly plastic immune cells in the tumor microenvironment (TME), which can be classified into two main phenotypes: classical activated M1 macrophages and alternatively activated M2 macrophages. As previously reported, M2-polarized TAMs play critical role in promoting the progression of non-small cell lung cancer (NSCLC) via secreting exosomes, but the detailed mechanisms are still largely unknown. In the present study, the THP-1 monocytes were sequentially induced into M0 and M2-polarized macrophages, and the exosomes were obtained from M0 (M0-exos) and M2 (M2-exos) polarized macrophages, respectively, and co-cultured with NSCLC cells (H1299 and A549) to establish the exosomes-cell co-culture system in vitro. As it was determined by MTT assay, RT-qPCR and Transwell assay, in contrast with the M0-exos, M2-exos significantly promoted cell proliferation, migration and epithelial-mesenchymal transition (EMT) process in NSCLC cells. Next, through screening the contents in the exosomes, it was verified that miR-155-5p was especially enriched in the M2-exos, and M2-exos enhanced cancer aggressiveness and tumorigenesis in in vitro NSCLC cells and in vivo xenograft tumor-bearing mice models via delivering miR-155-5p. The detailed molecular mechanisms were subsequently elucidated, and it was found that miR-155-5p bound with HuR to increase the stability and expression levels of VEGFR2, which further activated the tumor-promoting PI3K/Akt/mTOR signal pathway, and M2-exos-enhanced cancer progression in NSCLC cells were apparently suppressed by downregulating VEGFR2 and PI3K inhibitor LY294002 co-treatment. Taken together, M2-polarized TAMs secreted miR-155-5p-containing exosomes to enhanced cancer aggressiveness of NSCLC by activating the VEGFR2/PI3K/Akt/mTOR pathway in a HuR-dependent manner.