DataSheet_1_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液供应的肿瘤脉管系统，其形成过程不依赖血管内皮细胞。相反，血管生成拟态结构由分化后的肿瘤细胞（如鼻咽癌细胞）构建而成。近期研究表明，抗血管生成治疗未能改善患者——尤其是鼻咽癌患者——的总生存期，而血管生成拟态结构的存在可能是抗血管生成治疗耐药的原因之一。因此，研究鼻咽癌中血管生成拟态的形成机制具有重要意义。本研究通过生物信息学分析发现，microRNA-125a-3p（miR-125a）在正常鼻咽上皮组织中的表达水平高于鼻咽癌组织。体外实验证实，miR-125a可抑制鼻咽癌细胞的迁移及血管生成拟态形成，进一步研究确认TAZ是miR-125a的直接下游靶标。在此基础上，本研究人工工程化改造人间充质干细胞（human mesenchymal stem cells, MSCs），使其分泌高表达miR-125a的外泌体；用这类过表达miR-125a的外泌体处理鼻咽癌细胞，可减弱其迁移能力与血管生成拟态形成能力。此外，这类外泌体对鼻咽癌细胞迁移及血管生成拟态形成的抑制作用在体内实验中也得到了验证。综上，本研究表明，可利用MSCs制备高表达miR-125a的外泌体，这类外泌体可作为靶向鼻咽癌血管生成拟态的治疗性纳米颗粒，未来可作为抗血管生成治疗的补充手段。