MiR-181a delivered by hypoxic papillary thyroid cancer-secreted exosomes inhibits DACT2 by down-regulating MLL3, leading to YAP-VEGF pathway-mediated angiogenesis

Abstract Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, and angiogenesis plays critical roles in its recurrence and metastasis. In this study, we investigated the effects of hypoxia-induced exosomal microRNA-181 (miR-181a) from PTC on tumor growth and angiogenesis. Thyroid cancer-related differentially expressed miR-181a was identified by microarray-based analysis in the Gene Expression Omnibus (GEO) database. We validated that miR-181a was highly expressed in PTC cells, and even more so in cells cultured under hypoxic conditions, which also augmented exosome secretion from PTC cells. Exosomes extracted from PTC cells with manipulated miR-181a and MLL3 were subjected to normoxic or hypoxic conditions. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-181a inhibitor/mimic or siRNA-MLL3, or treated with exosomes from hypoxic PTC cells. Hypoxic exosomal miR-181a delivery promoted proliferation and capillary-like network formation in HUVECs. Mechanistically, miR-181a targeted and inhibited MLL3. Furthermore, miR-181a down-regulated DACT2, and up-regulated YAP and vascular endothelial growth factor (VEGF). Further, hypoxic exosomal miR-181a induced angiogenesis and tumor growth in vivo, which was reversed by hypoxic exosomal miR-181a inhibitor. In conclusion, exosomal miR-181a from hypoxic PTC cells promotes tumor angiogenesis and growth through MLL3 and DACT2 down-regulation, as well as VEGF up-regulation.