Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis in Vitro and in Vivo

We previously found that 19 microRNAs (miRNAs) significantly increased in the sera of hepatocellular carcinoma (HCC) patients. Here, we evaluated whether these miRNAs were secreted by HCC cells and contributed to tumor angiogenesis. High level of miR-210-3p (miR-210) was detected in the exosomes isolated from the sera of HCC patients and the conditioned media of hepatoma cells. Higher miR-210 level in serum was correlated with higher microvessel density in HCC tissues. Moreover, the HCC cell-secreted exosomes promoted in vitro tubulogenesis of endothelial cells, which was strengthened by overexpressing miR-210 in HCC cells but was attenuated by repressing miR-210 or DROSHA in HCC cells. This pro-tubulogenesis effect by HCC exosomes was also abrogated by antagonizing miR-210 in endothelial cells. Subsequent in vivo studies revealed that Matrigel plug and subcutaneous tumor xenografts treated with HCC cell-derived exosomal miR-210 displayed much more vessels. Furthermore, exosomal miR-210 could be delivered into endothelial cells and directly inhibited the expression of SMAD4 and STAT6, resulting in enhanced angiogenesis. Collectively, HCC cell-secreted exosomal miR-210 may be transferred into endothelial cells and thereby promotes tumor angiogenesis by targeting SMAD4 and STAT6. Our findings identify a novel mechanism of HCC angiogenesis and highlight the biological importance of exosomal miR-210.