放射诱导内皮细胞源Microvesicles通过TGF-β/Smad信号通路介导口腔癌放疗抗性的研究

项目名称： 放射诱导内皮细胞源Microvesicles通过TGF-β/Smad信号通路介导口腔癌放疗抗性的研究

项目编号： No.81502340

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 宋凯

作者单位： 青岛大学

项目金额： 18万元

中文摘要： 近年来研究认为，Microvesicles（MVs）可能是肿瘤复发和转移的基础，但目前对其分子机制知之甚少。我们前期研究发现放射诱导的内皮细胞源MVs中包含TGF-β1，本课题进一步提出假设“放疗诱导的内皮细胞源MVs通过转移TGF-β1至邻近肿瘤细胞，激活Smad2/3信号通路，进而介导肿瘤的上皮-间质转化（EMT）及放疗抗性，促进肿瘤侵袭及放疗后复发”。本课题围绕上述研究假设，重点探讨① 放射诱导的内皮细胞源MVs的提取、鉴定及其与口腔癌细胞相互作用方式；② 放射诱导的内皮细胞源MVs中TGF-β1的检测；③ TGF-β1/Smad信号通路在口腔癌细胞EMT及抗放疗特性中的作用；④口腔鳞状细胞癌标本中TGF-β1、MMP9、微血管密度（MVD）、p-Smad2的表达与临床、预后的关系。研究结果有可能揭示肿瘤术后放疗后复发、转移的一种全新机制，并为将来开发肿瘤放疗协同药物提供重要的思路.

中文关键词： 口腔癌；微颗粒；放疗抗性；内皮细胞；TGF-β/Smad；信号通路

英文摘要： Recently, it has been reported that Microvesicles (MVs) may play important roles in tumor relapse and metastasis. However, the detailed mechanism of MVs elicited relapse and metastasis remains unknown. Here, our previous study provided evidence that irradiation induced endothelial cell-derived MVs incorporated transforming growth factor-β1(TGF-β1). In this project, we hypothesize that irradiated endothelial cells delivered the TGF-β1 which were packaged into MVs to the adjacent tumor cells, and further activated the Smad2/3 signaling pathway to modulate the epithelial-to-mesenchymal transition (EMT) and radio-resistance of tumor cells. To confirm the above hypothesis, the present grant was designed to investigate ① the isolation of irradiation induced endothelial cell-derived MVs and how such MVs to fuse with oral cancer cells;② whether TGF-β1 was presented in irradiation induced endothelial cell-derived MVs; ③ regulatory role of TGF-β1/Smad in EMT and raidoresistance of tumor cells;④ correlation of the expression of TGF-β1、MMP9、MVD and p-Smad2 with prognosis of cancer. Our results expect to reveal a novel mechanism of tumor relapse and metastasis, and to provide a slight strategy to improve the radiotherapy of tumor.

英文关键词： oral cancer;microvesicels;radio-resistance;endothelial cells;TGF-β/Smad signaling pathway