Potential of peptide-engineered exosomes with overexpressed miR-92b-3p in anti-angiogenic therapy of ovarian cancer.

ABSTRACT

INTRODUCTION: Exosomal microRNA (miRNA) as a mediator of intercellular communication plays an essential part in tumor-relevant angiogenesis. Therapy against angiogenesis has been demonstrated to have a remarkable antitumor efficacy in various malignancies, but not as expected in ovarian cancer. METHODS: Exosomes were isolated by ultracentrifugation. Exosomal miRNA sequencing and gene function experiments were used to identify the differential expressed miRNAs in exosomes and their mRNA targets. SKOV3 cell line that stably overexpressed miR-92b-3p was constructed by lentivirus. In vitro, angiogenesis was analyzed by tube formation assay and migration assay. The angiogenic and antitumor effects in vivo were assessed in zebrafish and nude mouse models. Combination index was calculated to assess the synergetic inhibition of angiogenesis between miR-92b-3p and Apatinib. Peptides were conjugated with exosomal membranes to obtain engineered exosomes. RESULTS: Ovarian cancer cell-derived exosomes facilitated the angiogenesis and migration capability of vascular endothelial cells in vitro and in vivo. The expression of miR-92b-3p was much lower in ovarian cancer cell-derived exosomes than that in immortalized ovarian epithelial cell-derived exosomes. The exosomal miR-92b-3p modulated tumor-associated angiogenesis via targeting SOX4. Besides, Peptide-engineered exosomes with overexpressed miR-92b-3p showed the stronger abilities of anti-angiogenesis and antitumor than parental exosomes, whether alone or combined with Apatinib. CONCLUSIONS: Our findings demonstrate the effect and mechanism of exosomal miR-92b-3p from ovarian cancer cells on tumor-associated angiogenesis and the potential of artificially generated exosomes with overexpressed miR-92b-3p to be used as anti-angiogenic agent, which may provide a new approach for anti-angiogenic therapy of ovarian cancer.