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Cancer-Associated Fibroblast-Derived Exosomal miRNA-320a Promotes Macrophage M2 Polarization In Vitro by Regulating PTEN/PI3Kγ Signaling in Pancreatic Cancer.

ABSTRACT: Our previous study has indicated that cancer-associated fibroblasts (CAFs) play a crucial role in regulating gemcitabine resistance through transferring exosomal miRNA-106b to cancer cells. Tumor-associated macrophages (TAMs) are recently verified to facilitate gemcitabine resistance. However, the effect of CAFs in regulating TAMs function in pancreatic cancer (PCa) remains unclear. Here, primary CAFs were extracted from tumor tissues of PCa patients, and CAFs-derived exosomes (CAFs-Exo) were acquired and authenticated by transmission electron microscopy, qNano, and western blot analysis. The role of exosomal miRNA-320a in facilitating macrophage M2 polarization was investigated in vitro. We found that CAFs-derived conditioned medium (CM) possessed a higher potential to promote macrophage M2 polarization compared with normal fibroblasts (NFs) or PCa cell-derived CM. Furthermore, CAFs-Exo treatment polarized macrophage to M2 phenotype. miRNA-320a levels were remarkably increased in CAFs-Exo versus NFs-Exo. More important, miRNA-320a could be transferred from CAFs to macrophages through exosomes, and miRNA-320a overexpression in macrophages facilitated its M2 polarization. Functionally, miRNA-320a-overexpressed macrophages facilitated PCa cell proliferation and invasion. CAFs pretreated with miRNA-320a inhibitor reduced miRNA-320a expression in CAFs-Exo and led to decreased M2 macrophage polarization. Finally, we verified that miRNA-320a polarized macrophage to M2 phenotype by regulating PTEN/PI3Kγ signaling. Taken together, the current data demonstrated that CAFs-derived exosomal miRNA-320a facilitated macrophage M2 polarization to accelerate malignant behavior of PCa cells.

SUBMITTER: Zhao M

PROVIDER: S-EPMC9270150 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCirculating miRNAs are known to play important roles in intercellular communication. However, the effects of exosomal miRNAs on cells are not fully understood.MethodsTo investigate the role of exosomal miR-1246 in ovarian cancer (OC) microenvironment, we performed RPPA as well as many other in vitro functional assays in ovarian cancer cells (sensitive; HeyA8, Skov3ip1, A2780 and chemoresistant; HeyA8-MDR, Skov3-TR, A2780-CP20). Therapeutic effect of miR-1246 inhibitor treatment was tested in OC animal model. We showed the effect of OC exosomal miR-1246 uptake on macrophages by co-culture experiments.FindingsSubstantial expression of oncogenic miR-1246 OC exosomes was found. We showed that Cav1 gene, which is the direct target of miR-1246, is involved in the process of exosomal transfer. A significantly worse overall prognosis were found for OC patients with high miR-1246 and low Cav1 expression based on TCGA data. miR-1246 expression were significantly higher in paclitaxel-resistant OC exosomes than in their sensitive counterparts. Overexpression of Cav1 and anti-miR-1246 treatment significantly sensitized OC cells to paclitaxel. We showed that Cav1 and multi drug resistance (MDR) gene is involved in the process of exosomal transfer. Our proteomic approach also revealed that miR-1246 inhibits Cav1 and acts through PDGFβ receptor at the recipient cells to inhibit cell proliferation. miR-1246 inhibitor treatment in combination with chemotherapy led to reduced tumor burden in vivo. Finally, we demonstrated that when OC cells are co-cultured with macrophages, they are capable of transferring their oncogenic miR-1246 to M2-type macrophages, but not M0-type macrophages.InterpretationOur results suggest that cancer exosomes may contribute to oncogenesis by manipulating neighboring infiltrating immune cells. This study provide a new mechanistic therapeutic approach to overcome chemoresistance and tumor progression through exosomal miR-1246 in OC patients.

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Cancer-Associated Fibroblast-Derived Exosomal miRNA-320a Promotes Macrophage M2 Polarization In Vitro by Regulating PTEN/PI3Kγ Signaling in Pancreatic Cancer.

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