Exosomal miR-191 promotes colorectal cancer progression by inducing M2 macrophage polarization and inhibiting ferroptosis

BACKGROUND Multiple exosomal microRNAs were reported to have a significant role in colorectal cancer (CRC) cells. The function and mechanism of exosomal miR-191 in CRC have not been clearly elucidated. AIM To explore the roles of miR-191 in CRC. METHODS Supernatant exosomes from CRC cells were extracted and identified. After coculture, macrophage polarization was determined using flow cytometry for the markers cluster of differentiation (CD) 68 and CD163, enzyme-linked immunosorbent assay for the cytokines interleukin (IL)-4 and IL-10, western blotting for chitinase-like protein 3 and arginase-1 expression, and immunofluorescent staining for 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanine perchlorate. Reactive oxygen species (ROS) level, ferroptosis-related proteins (SLC7A11 and GPX4 ), and apoptosis were determined with flow cytometry, western blotting, and TUNEL staining. We performed in vivo experiments to determine the function of exosomal miR-191 and M2 macrophage polarization. RESULTS We successfully isolated exosomes from CRC cells. Inhibition of miR-191 in CRC cells suppressed M2 polarization of macrophages. After coculture of macrophages, inhibition of miR-191 induced ROS production, ferroptosis, and apoptosis of CRC cells. Silencing of exosomal miR-191 from CRC cells prevented M2 polarization of macrophages, and weakened CRC development by inducing ferroptosis. Exosomal miR-191 accelerated cancer progression in CRC nude mice by promoting M2 polarization of macrophages. CONCLUSION Inhibition of exosomal miR-191 attenuated CRC progression by inducing ferroptosis in macrophages. This study revealed a novel mechanism by which exosomal miR-191 modulates the tumor microenvironment.