Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis In Vitro and In Vivo.
Hepatocellular Carcinoma Cell-Secreted Exosomal MicroRNA-210 Promotes Angiogenesis In Vitro and In Vivo.
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肝细胞癌细胞分泌的外泌体 MicroRNA-210 在体外和体内促进血管生成
DOI：
10.1016/j.omtn.2018.02.014
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发表时间：
2018-06-01
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
Lin XJ;Fang JH;Yang XJ;Zhang C;Yuan Y;Zheng L;Zhuang SM
我们先前发现19个microRNAs(MiRNAs)在肝细胞癌患者的血清中显著增加。在这里，我们评估了这些miRNAs是否由肝癌细胞分泌，并有助于肿瘤血管生成。从肝癌患者血清和肝癌细胞条件培养液中分离到高水平的miR-210-3p(miR-210)。血清miR-210水平越高，肝细胞癌组织中微血管密度越高。此外，肝癌细胞分泌的外切体在体外促进内皮细胞的小管生成，在肝癌细胞中过表达miR-210可增强这种作用，但在肝癌细胞中抑制miR-210或DROSHA可减弱这种作用。通过拮抗内皮细胞中的miR-210，肝癌外体的这种促小管生成作用也被取消。随后的体内研究显示，用肝癌细胞衍生的外体miR-210治疗的Matrigel Plug和皮下肿瘤移植瘤显示了更多的血管。此外，外体miR-210可被转导入内皮细胞，直接抑制Smad4和STAT6的表达，从而促进血管生成。总的来说，肝癌细胞分泌的外体miR-210可能被转移到内皮细胞，从而通过靶向Smad4和STAT6促进肿瘤血管生成。我们的发现确定了一种新的肝癌血管生成机制，并强调了外体miR-210的生物学重要性。
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.
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影响因子：
21.3
作者：
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影响因子：
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作者：
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