TAM-derived extracellular vesicles containing microRNA-29a-3p explain the deterioration of ovarian cancer

Abstract

Extracellular vesicles (EVs) secreted from tumor-associated macrophages (TAMs) are known to generate an immune-suppressive environment conducive to the development of ovarian cancer (OC). We tried to elucidate the role of TAM-derived exosomal microRNA (miR)-29a-3p in OC. miR-29a-3p, forkhead box protein O3 (FOXO3), and programmed death ligand-1 (PD-L1) expression was determined and their interactions evaluated. EVs were isolated, followed by determination of the uptake of EVs by OC cells, after which the proliferation and immune escape facilities of the OC cells were determined. OC xenograft models were constructed with EVs in correspondence with in vivo experiments. Overexpressed miR-29a-3p was detected in OC, and miR-29a-3p promoted OC cell proliferation and immune escape. EVs derived from TAMs enhanced the proliferation of OC cells. miR-29a-3p was enriched in TAM-EVs, and TAM-EVs delivered miR-29a-3p into OC cells. Downregulated FOXO3 was identified in OC, whereas miR-29a-3p targeted FOXO3 to suppress glycogen synthase kinase 3β (GSK3β) activity via the serine/threonine protein kinase (AKT)/GSK3β pathway. Inhibition of TAM-derived exosomal miR-29a-3p decreased PD-L1 to inhibit OC progression through the FOXO3-AKT/GSK3β pathway in vitro and in vivo. Taken together, the current studies highlight the FOXO3-AKT/GSK3β pathway and the mechanism by which TAM-derived exosomal miR-29a-3p enhances the expression of PD-L1 to facilitate OC cell proliferation and immune escape.

Keywords

• tumor-associated macrophage-derived extracellular vesicles
• microRNA-29a-3p
• forkhead box protein O3
• serine/threonine protein kinase/glycogen synthase kinase 3β
• programmed death ligand-1
• ovarian cancer