DataSheet_3_Mesenchymal Stem Cells Inhibits Migration and Vasculogenic Mimicry in Nasopharyngeal Carcinoma Via Exosomal MiR-125a.csv

Vasculogenic mimicry (VM) is a kind of tumor vasculature providing blood supply for tumor growth, and the formation of VM is independent of vascular endothelial cells. Instead, VM structures are formed by differentiated tumor cells such as nasopharyngeal carcinoma cells. Recently, studies have shown that anti-angiogenic therapy failed to improve the overall survival for patients, namely, nasopharyngeal carcinoma patients. The existence of VM structure is probably one of the reasons for resistance for anti-angiogenic therapy. Therefore, it is important to study the mechanism for VM formation in nasopharyngeal carcinoma. In this study, the bioinformatic analysis revealed that microRNA-125a-3p (miR-125a) was highly expressed in normal nasopharyngeal epithelial tissue than in nasopharyngeal carcinoma. An in vitro study demonstrated that miR-125a plays an inhibitory role in nasopharyngeal carcinoma cell migration and VM formation, and further studies confirmed that TAZ is a direct downstream target for miR-125a. On this basis, we artificially engineered human mesenchymal stem cells (MSCs) to generate exosomes with high miR-125a expression. Treatment with these miR-125a-over-expressing exosomes attenuated the migration and VM formation in nasopharyngeal carcinoma cells. In addition, the inhibitory role of these exosomes on VM formation and migration in nasopharyngeal carcinoma was also confirmed in vivo. Overall, the current study shows that MSCs can be utilized to generate exosomes with high miR-125a level, which could be therapeutic nanoparticles targeting VM formation in nasopharyngeal carcinoma and used as a complement to anti-angiogenic therapy in the future.

血管生成拟态（Vasculogenic mimicry, VM）是一类为肿瘤生长提供血供的肿瘤脉管系统，其形成过程不依赖血管内皮细胞。相反，VM结构由分化成熟的肿瘤细胞（如鼻咽癌细胞）构建而成。
近期研究显示，抗血管生成治疗未能改善鼻咽癌患者的总生存率，而VM结构的存在可能是该治疗产生耐药性的原因之一。因此，探究鼻咽癌中VM形成的机制具有重要的临床意义。
本研究通过生物信息学分析发现，微小RNA-125a-3p（microRNA-125a-3p, miR-125a）在正常鼻咽上皮组织中的表达水平显著高于鼻咽癌组织。体外实验证实，miR-125a可对鼻咽癌细胞的迁移能力及VM形成起到抑制作用；进一步研究确认，TAZ是miR-125a的直接下游靶基因。
在此基础上，我们通过人工工程化改造人源间充质干细胞（human mesenchymal stem cells, MSCs），制备得到高表达miR-125a的外泌体（exosomes）。使用此类过表达miR-125a的外泌体进行处理后，鼻咽癌细胞的迁移能力与VM形成均被显著抑制。
此外，这类外泌体对鼻咽癌细胞迁移及VM形成的抑制效应，在体内实验中也得到了验证。
综上，本研究表明，人源间充质干细胞可用于制备高表达miR-125a的外泌体，此类外泌体可作为靶向鼻咽癌VM形成的治疗性纳米颗粒，未来有望作为抗血管生成治疗的补充手段。