缺氧环境诱导的外泌体miR-133b调控HuR/Vav3影响乳头状甲状腺癌的转移机制研究

乳头状甲状腺癌(PTC) 发病率呈逐年上升趋势，多数患者预后良好。但晚期肿瘤出现侵袭和转移能力增强，传统治疗手段效果欠佳。课题组近期收集PTC 原位癌和转移癌分别做蛋白芯片和miRNA芯片检测，发现 HuR和Vav3 在转移癌中高表达，而miR-133b 低表达。为了模拟肿瘤缺氧微环境，体外缺氧诱导分泌外泌体，发现miR-133b在缺氧诱导的外泌体中低表达，并且促进PTC 细胞的迁移。课题组通过生物信息学分析和荧光素酶检测发现miR-133b调控HuR的3’UTR 以及染色质免疫共沉淀检测HuR 调控Vav3的表达。而过表达Vav3 能够激活Rac1/JNK 通路，促进PTC 细胞迁移。基于以上结果我们推测缺氧环境介导外泌体miR-133b通过调控HuR的表达，进而调控Vav3 /Rac1/JNK信号通路最终导致了PTC迁移、侵袭和转移，为探索PTC的发生发展提供重要的理论基础。

The incidence of papillary thyroid cancer (PTC) is increasing rapidly, and most patients have a good prognosis after treatment. Although most patients have a good prognosis when treated with traditional therapy, it is difficult to achieve satisfactory results in progress and metastatic tumour. The research team recently collected PTC tissue for protein chip and miRNA microarray examination and found that HuR and Vav3 are highly expressed in metastatic tumor, while miR-133b is lowly expressed. When hypoxia induced secretion of exosomes in vitro, it was found that miR-133b is underexpressed in hypoxia-induced exosomes and promotes migration of PTC cells. The bioinformatics analysis and luciferase assay showed that miR-133b regulates the 3'UTR of HuR and chromatin immunoprecipitation to detect the expression of Vav3 by HuR. Overexpression of Vav3 activates the Rac1/JNK pathway and promotes PTC cell migration. Based on the above results, we hypothesized that the hypoxic environment mediates the expression of HuR by exosome miR-133b, and then regulates the Vav3 /Rac1/JNK signaling pathway, which ultimately leads to the occurrence of PTC migration, invasion and metastasis.