miRNA-126对胶质瘤干细胞向血管周细胞转分化的调控作用及机制研究

By grants from the National Natural Science Foundation (81001127), we found that glioma stem cells contributed to tumor neovascularization via production of proangiogenic factors and transdifferentiation into endothelial cells. We also discovered that miRNA-126 inhibited glioma stem cell-induced neovascularization by targeting PIK3CD. These results have been published in Stem Cells and J Pathol. Interestingly, expression of miRNA-126 in glioblastoma correlated negatively with the number of pericytes that are proved crucial in tumor angiogenesis. Over-expression of miRNA-126 in glioma stem cells effectively decreased pericytes in xenografts. Based on our results and the new finding of cancer stem cells that were capable of generating cells expressing several pericyte markers, we propose that miRNA-126 may regulate glioma stem cells to give rise to pericytes through targeting PIK3CD, followed by the activation of PI3K/Akt pathway. In this project, we will construct new models for observation the potential of cancer stem cells to generate pericytes, and explore the mechanism by which miRNA-126 regulates glioma stem cells to transdifferentiate into pericytes. Our results may provide new insights that will enrich the theory of tumor neovascularization to facilitate the development of novel anti-angiogenic strategies.

在青年基金项目资助下，我们发现胶质瘤干细胞诱导和转分化为血管内皮参与血管新生的作用及机制，证明miRNA-126抑制胶质瘤干细胞促血管新生作用，其靶基因是PIK3CD，在Stem Cells和J Pathol发表SCI论文2篇。研究中新发现miRNA-126表达量与胶质瘤血管周细胞数量呈负相关，过表达miRNA-126的胶质瘤干细胞形成的移植瘤中周细胞减少。因周细胞在血管生成中十分关键，我们基于青年基金工作基础，结合肿瘤干细胞可转分化为周细胞的新进展, 提出“胶质瘤干细胞miRNA-126低表达，失去对靶基因PIK3CD的抑制作用，使PI3K/Akt通路异常活化，促进胶质瘤干细胞向血管周细胞转分化”的科学假设。拟建立肿瘤干细胞向周细胞转分化新研究模型，探明miRNA-126对胶质瘤干细胞向周细胞转分化的调控作用及机制，以期丰富胶质瘤干细胞参与血管新生的理论体系，为抗血管新生治疗提供新途径。

血管周细胞是微血管壁的重要成份，已有研究表明，肿瘤干细胞 (cancer stem cells, CSCs) 可以转分化为周细胞，直接构建肿瘤血管。但是，这些CSCs来源的周细胞在构建肿瘤微循环中的重要性、CSCs向周细胞转分化的调控机制及治疗意义尚不清楚。本项目针对miRNA-126对胶质瘤干细胞 (glioma stem cells, GSCs) 向周细胞转分化的调控作用、机制及治疗学意义开展研究。成功从人脑胶质瘤组织中分选获得血管周细胞，并构建了GSCs向血管周细胞转分化体内外示踪模型；发现miR-126通过靶向HIP1抑制GSCs 干性和VEGF分泌而抑制GSCs向血管周细胞转分化，靶向GSCs miRNA-126，联合抗血管生成药物贝伐单抗（bevacizumab）能够有效抑制GSCs移植瘤生长及血管生成；寻获反映胶质瘤血管丰富性和复杂性的定量指标，证明“异型血管”周细胞覆盖率高，富含周细胞的“异型血管”的多少可预测胶质瘤患者化疗效果；发现miRNA-663通过与CXCR4 CDS区结合抑制CXCR4表达，进而调控胶质母细胞瘤恶性行为。结合自身工作及国内外新进展，对肿瘤干细胞与血管微环境之间的调控关系进行综述。以上研究结果共发表SCI论文2篇，影响因子均大于5，申报发明专利1件。此外，尚有Lab Invest修回论文1篇，投稿阶段论文1篇。参加会议交流6次。培养“干细胞青年研究员奖”获得者1名、“中国病理研究杰出青年奖”获得者1名、博士生5名，硕士生1名，省部级优秀博士论文奖获得者1名。