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Abstract：
This study aimed to investigate the role of miR-558 in tumor angiogenesis by targeting heparinase (HPSE) in tongue squamous cell carcinoma (TSCC)-derived exosomes. In the present study, the role of exosome miR-558 in angiogenesis in vitro and in vivo was investigated by cell proliferation, migration, tube formation, subcutaneous tumor formation in mice, and in vivo Matrigel plug assay. The target genes of miR-558 were detected by means of dual luciferase assay. It was found that TSCC cells secrete miR-558 into the extracellular environment, with exosome as the carrier. Human umbilical vein endothelial cells (HUVEC) ingested exosomes, which not only increased the expression level of miR-558, but also enhanced their proliferation, migration, and tube formation functions. In vivo Matrigel plug assay demonstrated that TSCC cell-derived exosome miR-558 promoted neovascularization in vivo. Compared with negative control cells, TSCC cells overexpressing miR-558 formed subcutaneous tumors in nude mice, with larger volume, heavier mass, and more vascularization. Dual luciferase assay confirmed that HPSE was the direct target gene regulated by miR-558. HPSE promoted the proliferation, migration, and tube formation of HUVECs, and the knockout of HPSE could downregulate the pro-angiogenic effect of miR-558. In summary, miR-558 in TSCC exosomes promotes the proliferation, migration, and tube formation of HUVECs by targeting HPSE, and enhancing tumor angiogenesis.
摘要：
本研究通过靶向舌鳞状细胞癌(TSCC)外泌体肝素酶(HPSE)研究miR-558在肿瘤血管生成中的作用。在本研究中,通过细胞增殖研究外泌体miR-558在体外和体内血管生成中的作用，迁移,管形成,小鼠皮下肿瘤形成，和体内基质胶塞测定。采用双荧光素酶法检测miR-558的靶基因。发现TSCC细胞分泌miR-558进入细胞外环境,外泌体作为载体。人脐静脉内皮细胞（HUVEC）摄入外泌体，这不仅增加了miR-558的表达水平，而且增强了它们的增殖，迁移,和管形成功能。体内基质胶塞测定证明TSCC细胞来源的外泌体miR-558促进体内新血管形成。与阴性对照细胞相比，过表达miR-558的TSCC细胞在裸鼠中形成皮下肿瘤，体积较大，质量更重,和更多的血管化。双荧光素酶检测证实HPSE是miR-558调控的直接靶基因。HPSE促进了扩散，迁移,和HUVECs的管形成，HPSE的敲除可以下调miR-558的促血管生成作用。总之,miR-558在TSCC外泌体中促进增殖,迁移,通过靶向HPSE形成HUVECs的管，并增强肿瘤血管生成。
