MiR-382 Inhibits Breast Cancer Progression and Metastasis by Affecting the M2 Polarization of Tumor-Associated Macrophages by Targeting PGC-1 Alpha

Macrophages are principal immune cells with a high plasticity in the human body that can differentiate under different conditions in the tumor microenvironment to adopt two polarized phenotypes with opposite functions. Therefore, converting macrophages from the immunosuppressive phenotype (M2) to the inflammatory phenotype (M1) is considered a promising therapeutic strategy for cancer. However, the molecular mechanisms underlying this conversion process have not yet been completely elucidated. In recent years, microRNAs (miRNAs or miRs) have been shown to play key roles in regulating macrophage polarization through their ability to modulate gene expression. In the present study, it was found that miR-382 expression was significantly downregulated in tumor-associated macrophages (TAMs) and M2-polarized macrophages in breast cancer. In vitro, macrophage polarization toward the M2 phenotype and M2-type cytokine release were inhibited by transfection with miR-382-overexpressing lentivirus. Similarly, the overexpression of miR-382 inhibited the ability of TAMs to promote the malignant behaviors of breast cancer cells. In addition, peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) was identified as the downstream target of miR-382 and it was found that PGC-1 alpha affected macrophage polarization by altering the metabolic status. The ectopic expression of PGC-1 alpha restored the phenotype and cytokine secretion of miR-382-overexpressing macrophages. Furthermore, PGC-1 alpha expression reversed the miR-382-induced changes in the metabolic state of TAMs and the effects of TAMs on breast cancer cells. Of note, the in vivo growth and metastasis of 4T1 cells were inhibited by miR-382-overexpressing TAMs. Taken together, the results of the present study suggest that miR-382 may alter the metabolic status of macrophages by targeting PGC-1 alpha, thereby decreasing the proportion of TAMs with the M2 phenotype, and inhibiting the progression and metastasis of breast cancer.