Epithelial ovarian cancer-secreted exosomal miR-222-3p induces polarization of tumor-associated macrophages

Abstract

Cancer secreted exosomal miRNAs are emerging as mediators between tumor-stoma crosstalk. Here, we show epithelial ovarian cancer (EOC)-derived exosomes activated macrophages to a tumor-associated macrophage (TAM)-like phenotype with SOCS3/STAT3 pathway involvement, which could facilitate the progression of cancer. MiR-222-3p was enrichment in exosomes released from EOC cells and it could be transferred to macrophages. Overexpression of miR-222-3p in macrophages induced polarization of the M2 phenotype. Luciferase assay verified miR-222-3p targeted SOCS3 genes and expression of SOCS3 was decreased after transfection with a miR-222-3p mimic. Down-regulation of SOCS3 correlated with an increased expression of STAT3 activation. MiR-222-3p could be detected in the exosomes from serum and its levels were related to EOC. These observations propose tumor-derived exosomal miR-222-3p is an effective regulator in the polarization of tumor-promoting M2 macrophages and may be a biomarker of EOC.

The role of cancer-derived microRNAs in cancer immune escape

“…Abundant M2-like TAMs in the tumor microenvironment promote carcinogenesis by inducing angiogenesis, suppressing anti-cancer immune response, and antagonizing cancer cell apoptosis [143]. Epithelial ovarian cancer cells induced the polarization of TMAs toward M2-like phenotype via secreting exosomal miR-222-3p and miR-940 [127,128]. Besides, under hypoxic condition, epithelial ovarian cancer cell-secreted exosomes contained miRNAs such as miR-21-3p, miR-125b-5p, and miR-181d-5p, which enhanced the polarization of M2-like TAMs and promoted cancer growth [129].…”

“…Immunosuppressive [125] miR-24-3p NPC Immunosuppressive [126] miR-891a NPC Immunosuppressive [126] miR-106a-5p NPC Immunosuppressive [126] miR-20a-5p NPC Immunosuppressive [126] miR-1908 NPC Immunosuppressive [126] TAMs miR-222-3p EOC Immunosuppressive [127] miR-940 EOC Immunosuppressive [128] miR-21-3p EOC Immunosuppressive [129] miR-125b-5p EOC Immunosuppressive [129] miR-181d-5p EOC Immunosuppressive [129] miR-21 Head and neck cancer Immunosuppressive [130] miR-1246 Colon cancer Immunosuppressive [131] miR-16 Breast cancer Immunostimulatory [132] MDSCs miR-107 Gastric cancer Immunosuppressive [133] miR-21 OSCC Immunosuppressive [134] miR-21 Glioma Immunosuppressive [135] miR-10a Glioma Immunosuppressive [135] miR-29a Glioma Immunosuppressive [136] miR-92a Glioma Immunosuppressive [136] miR-155 CLL Immunosuppressive [137] CAFs miR-27a Gastric cancer Immunosuppressive [138] miR-1247-3p HCC Immunosuppressive [139] miR-21 HCC Immunosuppressive [140] NPC nasopharyngeal carcinoma, TAM tumor-associated macrophage, EOC epithelial ovarian cancer, MDSC myeloid-derived suppressor cell, OSCC oral squamous cell carcinoma, CLL chronic lymphocytic leukemia, CAF cancer-associated fibroblast, HCC hepatocellular carcinoma M2-like phenotype and suppressing the expression of M1 phenotype-associated markers [130]. Similarly, Cooks et al observed that cancer cells harboring TP53 mutation could reprogram neighboring TAMs into pro-tumor state via secreting miR-1246-enriched exosomes [131].…”

Potential mechanisms of microRNA mobility

“…A plenty of studies have proven the exosome mediated functional shuttling of miRNA in multiple cell types . For example, the uptake of miR‐222‐3p enriched exosomes by macrophages, released from ovarian cancer cells, led to stimulation of the STAT3 pathway which in turn promotes macrophage activation . Likewise, exosomal miRNA cargos were found to be delivered from ependymal cells into the brain by crossing the blood brain barrier, triggering downregulation of miRNA specific target genes .…”

Cross‐Talk Between Hypoxia and the Tumour via Exosomes

“…A recent study established the role of EOC-derived exosomes in mediating the activation of macrophages to a tumour-associated macrophage (TAM) state [94]. They also demonstrated that SKOV-3 cells when grown with conditioned media from the transformed macrophages were more likely to migrate and proliferate.…”