放疗联合替莫唑胺化疗是胶质母细胞瘤临床治疗的重要策略，替莫唑胺(Temozolomide,TMZ)耐药是影响临床疗效的关键。除DNA修复酶O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）启动子甲基化外，胶质母细胞瘤中还存在MGMT非依赖性TMZ耐药机制。已有研究表明，非胶质瘤干细胞向胶质瘤干细胞转化过程中，细胞对TMZ的耐药性增加，提示胶质瘤干细胞是TMZ耐药的关键细胞。因此，找到调控胶质瘤干细胞TMZ耐药的关键分子至关重要。我们前期构建了TMZ耐药细胞系，基因芯片分析发现HOXA5表达在耐药细胞中显著上升，继而又证明HOXA5在胶质瘤干细胞中高表达，提示HOXA5可能是非胶质瘤干细胞向胶质瘤干细胞转化并导致TMZ耐药的关键分子。本项目拟在前期工作基础上，研究 HOXA5调控胶质瘤细胞替莫唑胺耐药的重要作用；寻找HOXA5的关键下游分子及作用机制；分析HOXA5指导化疗用药以及作为预后指标的临床意义；探讨并明确靶向HOXA5及相关分子在胶质母细胞瘤中的临床治疗价值。

Radiotherapy combined with Temozolomide is the main strategy for the clinical treatment of glioblastoma, and the occurrence of TMZ resistance is the key to the clinical efficacy. In addition to MGMT promoter methylation, there is still MGMT independent mechanism of TMZ resistance in glioblastoma. Previous studies have shown that resistance to TMZ increased during the transformation of non-GSCs into GSCs, suggesting that GSCs are the key cells of TMZ resistance. Therefore, it is very important to find the key molecules that regulate the transformation of non glioma stem cells into glioma stem cells in TMZ resistant environment. We previously constructed TMZ cell lines ,and the gene chip analysis results show that HOXA5 is significantly up-regulated in the process of drug resistance. Next we prove that HOXA5 is highly expressioned in glioma stem cells, suggesting that HOXA5 plays an important role in the regulation of TMZ resistance induced by the transformation of glioma stem cells into glioma stem cells. Based on the previous work, we plan to to study the role of HOXA5 in regulating the resistance of glioma cells to TMZ, seek the key downstream molecules of HOXA5 in this process, analysis the clinical significance of HOXA5 in guiding chemotherapy and prognosis of GBM patients. Our work is not just illuminate the function of HOXA5 in TMZ resistance, but also provide clues for clinical application of combined TMZ targeting HOXA5 therapy.