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.

Evaluation of the potential diagnostic role of the Lnc-MIAT, miR-29a-3p, and FOXO3a ceRNA networks as non-invasive circulatory biomarkers in ductal carcinoma breast cancer

“…In another similar study, dual-luciferase demonstrated miRNA-29a-3p has a targeting relationship with FOXO3a in OC (ovarian cancer) and, according to western blot, overexpression of miRNA-29a-3p inhibited the expression of FOXO3a and downregulation of miRNA-29a-3p elevated the expression of FOXO3a. Based on these results, they showed that FOXO3a could be targeted by miRNA-29a-3p [52].…”

Exosome-Mediated Immunosuppression in Tumor Microenvironments

“…Exosomes derived from M2 macrophages carry miR-155-5p, which induces immune escape and promotes the development of colon cancer by impairing the ZC3H12B-mediated stability of IL-6 [ 97 ]. Besides, exosomes enriched with miR-29a-3p mediate the FOXO3-AKT/GSK3β axis and improve the expression of PD-L1 in ovarian cancer cells, consequently promoting the proliferation and immune escape of ovarian cancer cells [ 98 ]. In addition, exosomes derived from M2 macrophages shuttle miR-21 to promote the survival, proliferation, migration, and invasion of glioma cells through decreased expression of paternally expressed gene 3 (PEG3).…”

Extracellular vesicle contents as non-invasive biomarkers in ovarian malignancies

“…109 In addition, tumor-associated macrophages releasing microRNA-29a-3pcontaining EVs are found to upregulate the PD-L1 to facilitate ovarian cancer cell proliferation and immune escape. 110 Tumor cells are known to cause T cell suppression, but the mechanism describing EV-based T cell suppression has only been explored recently. This can be exemplified by the upregulation of Siglec-10 on T cells by EVs derived from malignant ascites.…”

“… 109 In addition, tumor-associated macrophages releasing microRNA-29a-3p-containing EVs are found to upregulate the PD-L1 to facilitate ovarian cancer cell proliferation and immune escape. 110 …”