HIF1α/HIF2α-Notch信号通路经EGF/FGF2介导胶质瘤细胞缺氧逆分化分子机制研究

既往认为缺氧微环境维持胶质瘤干细胞干性是肿瘤恶性进展的根本原因。然而，我们前期证实除外胶质瘤干细胞，普通分化胶质瘤细胞缺氧下可逆分化形成肿瘤干样细胞，进而促使肿瘤恶性进展，但机制不明。HIF1α/HIF2α-Notch及EGF/FGF2缺氧环境下可高表达，但是否调控胶质瘤细胞缺氧逆分化目前未有报道。预实验证实敲除分化胶质瘤细胞HIF1α/HIF2α表达后继续缺氧培养可下调EGF/FGF2、Notch表达，同时降低细胞悬浮成球能力；添加EGF/FGF2后，Notch表达升高并增强细胞悬浮成球能力。据此，我们推测：HIF1α/HIF2α-Notch通路经EGF/FGF2介导胶质瘤细胞缺氧逆分化。项目中HIF1a/HIF2a-EGF/FGF2-Notch分子网络在胶质瘤细胞缺氧逆分化现象中的证实为胶质瘤的恶性进展提供了新的理论认知，也为胶质瘤的临床综合治疗提供了新的思考方向及治疗靶点。

Hypoxia microenvironment plays a vital role in stemness maintenance of glioma stem cells (GSCs). We found GSCs can be induced through dedifferentiation from differentiated glioma cells, but we don’t clear the mechanism why this phenomenon formed. Traditional studies showed HIF1α/HIF2α-Notch pathway made great contributions to stemness maintenance at hypoxia conditions. Besides, the expression of EGF and FGF2 increased significantly at hypoxia. According to our recent study we found the expression of EGF, FGF2 and Notch decreased after HIF1a and HIF2a were interference; the results also showed the formation rate of neurospheres declined, and its rate increased significantly when we added EGF and FGF2 into culture medium of ShRNA-HIF1a or Sh-RNA-HIF2a. Therefore we speculate that HIFs-EGF/FGF2-Notch pathway plays an important role in the process of dedifferentiation of differentiate glioma cells in hypoxia. The dedifferentiation study can challenge traditional theory that only cancer stem cells promote tumor malignant and it provides us new strategy to glioma treatment.