Cancer cell-derived exosomal miR-34a inhibits the malignant progression of pancreatic adenocarcinoma cells by restraining the M2 polarization of macrophages.

This study aimed to investigate the crosstalk mechanism between pancreatic cancer (PAC) cells and M2 tumor-associated macrophages induced by tumor-derived exosomal miR-34a. MicroRNA and mRNA expression levels were detected using RT-qPCR. Cell Counting Kit-8, wound-healing, transwell assays and flow cytometry were respectively employed to assess cell proliferation, migration, invasion and apoptosis. Enzyme-linked immunosorbent assay was utilized to determine cytokine secretion. Transmission electron microscopy and nanoparticle tracking analyses were performed to detect the exosome morphology and particle size. Phagocytosis of exosomes by macrophages was verified by PKH26 labeling. The effects of exosome-treated macrophages on the epithelial-mesenchymal transition, invasion, and migration of PANC-1 cells were investigated using coculture experiments. The identification of miR-34a's potential targets were determined with TargetScan and validated by a dual-luciferase reporter assay. miR-34a was expressed at low levels in PAC tissues, cells, and exosomes. The overexpression of miR-34a restrains the malignant progression of PANC-1 cells. After miR-34a-overexpressed PANC-1-derived exosomes were phagocytosed by macrophages, the process of M2 polarization in macrophages was obstructed, leading to the suppression of epithelial-mesenchymal transition, migration, and invasion of the cocultured PANC-1 cells. Suppressor of cytokine signaling 3 is a direct target of miR-34a. MiR-34a negatively modulates the suppressor of cytokine signaling 3 to prevent the M2 polarization of macrophages by engaging the Janus kinase/signal transducers and activators of the transcription pathway and influencing the malignancy of PAC cells.  miR-34a in cancer cell-derived exosomes inhibits the malignant progression of pancreatic cancer cells by restraining M2 polarization of macrophages.