恶性胶质瘤对替尼泊苷的敏感性受MCM7-Cyclin D1/CDK4调控的机制研究

Mechanisms of malignant glioma chemotherapy resistance are the focus and difficulty of clinical studies. To investigate the specific chemotherapy resistance related target is of great value for individual target therapy. Teniposide is one of the commonly used chemotherapeutic drugs. Previous studies showed that sensitivity of glioblastoma (GBM) to teniposide closely correlated with miR-21 as well as its target gene LRRFIP1. Further studies revealed that Minichromosome maintenance protein 7 (MCM7) was the downstream molecule of LRRFIP1 and positively correlated with LRRFIP1 expression. Immunohistochemical studies implied that MCM7 negatively correlated with GBM patient survival and was possibly involved in regulating GBM chemotherapy resistance to teniposide. Besides, cyclinD1 positively correlated with the expression levels of MCM7 and negatively correlated with GBM patient survival. On this basis, we plan to employ genetic manipulation and chromatin co-immunoprecipitation techniques to explore the relationship between LRRFIP1 and MCM7 as well as the roles of MCM7 and Cyclin D1 in chemotherapy resistance to teniposide. We expect to discover specific teniposide chemotherapy resistance related genes, which will provide the theoretic evidence and basis for individualized treatment.

恶性胶质瘤的化疗耐药机制是临床研究的重点和难点，研究化疗耐药相关的特异性靶标在个体化靶向治疗中具有重要意义。替尼泊苷是临床常用的化疗药物之一，前期研究显示：胶质母细胞瘤（GBM）对替尼泊苷的敏感性与miR-21及其靶基因LRRFIP1密切相关。进一步研究发现LRRFIP1的下游分子为微染色体维持蛋白7（MCM7），且MCM7和miR-21的表达水平呈正相关。免疫组化结果亦提示：MCM7的表达水平与GBM患者的生存期呈反比关系，且可能参与调控GBM对替尼泊苷的化疗耐药；此外，CyclinD1的表达水平与MCM7呈正相关，与GBM患者的生存期亦呈反比关系。在此基础上，本项目拟利用基因操作、染色质免疫共沉淀等技术，探索：1、LRRFIP1与MCM7的关系；2、MCM7和Cyclin D1在替尼泊苷耐药中的协同作用机制。期望发现替尼泊苷耐药相关的特异性分子靶标,为个体化治疗提供理论依据和研究基础。