Bladder cancer cell-secreted exosomal miR-21 activates the PI3K/AKT pathway in macrophages to promote cancer progression

摘要

Tumour-associated macrophages (TAMs) compose a major component of the tumour microenvironment and form in this microenvironment prior to cancer metastasis. However, the detailed mechanisms of TAM remodelling in the context of bladder cancer have not been clearly defined. The present study collected exosomes from the conditioned medium of human bladder T24 cancer cells. The effects of macrophages treated with exosomes derived from T24 cells on bladder cancer cell migration and invasion were analysed by Transwell assays. The expression levels of endogenous and exosomal microRNA-21 (miR-21) were examined by reverse transcription-quantitative PCR, while the expression level of the target protein was analysed by western blot analysis. Luciferase reporter plasmids and mutants were used to confirm direct targeting. The effects of miR-21 on bladder cancer cell migration and invasion were analysed by Transwell and Matrigel assays following miR-21 transfection. It was identified that exosomes derived from bladder cancer cells polarized THP-1 cell-derived macrophages into the M2 phenotype, and TAM-mediated pro-migratory and pro-invasive activity was determined. Moreover, it was found that miR-21 was highly expressed in exosomes derived from bladder cancer cells as well as in macrophages treated with exosomes. In addition, macrophages transfected with miR-21 exhibited M2 polarization and promoted T24 cell migratory and invasive ability. Mechanistically, exosomal miR-21 derived from bladder cancer cells inhibited phosphatase and tensin homolog activation of the PI3K/AKT signalling pathway in macrophages and enhanced STAT3 expression to promote M2 phenotypic polarization. The present results suggest that exosomal miR-21 can promote cancer progression by polarizing TAMs.