Exosomal miR-499a-5p Inhibits Endometrial Cancer Growth and Metastasis via Targeting VAV3

The current therapeutic strategies for endometrial cancer are limited and unsatisfactory. Accumulating evidence suggest that microRNAs (miRNAs) participate in tumor growth and metastasis. Mesenchymal stem cells (MSCs) derived exosomes (Exos) are considered as better miRNA delivery vehicles. Here, we investigated the therapeutic effect of exosomal miR-499a-5p (miR-499) in human endometrial cancer metastasis.

Microarray analysis and RT-PCR were performed to detect the relative expression of miR-499 in endometrial cancer tissues and cell lines. MSC-derived Exos were characterized by transmission electron microscope (TEM), Western blot (WB), and nanoparticle tracking analysis (NTA). miR-499 was loading into Exos using electroporation. Cell proliferation and angiogenesis capacity were tested by 5-ethynyl-29-deoxyuridine (EdU) assay and tube formation assay, respectively. Dual-luciferase reporter assay (DLR) was used to confirm the connection of miR-499 and VAV3.

We found that the expression of miR-499 was significantly downregulated in cancer tissues compared with adjacent tissues in endometrial cancer patients. Moreover, exosomal miR-499 not only dramatically suppressed endometrial cancer cells proliferation, endothelial cells tube formation in vitro, but also inhibited tumor growth and angiogenesis in vivo. In addition, we confirmed that miR-499 directly targets the 3'UTR sequence of VAV3.

The novel identified exosomal miR-499 functions as a tumor suppressor in endometrial cancer though regulating VAV3, and these findings could be a valid molecular target for endometrial cancer therapy.