EZH2介导骨肉瘤干细胞对化疗不敏感及机制研究

Accumulated evidence indicates that the existence of cancer stem cells(CSC) is the most important reason for the re-initiation, drug resistance and clinical relapse of osteosarcoma. However the molecular mechanism for the drug resistance of cancer stem cells remain elucidated. Our preliminary data suggests that EZH2 is up-regulated in osteosarcoma stem cells and either inhibition of EZH2 activity or silence of EZH2 expression improves their chemotheraphy sensitivity, suggesting the involvement of EZH2 in drug resistance of osteosarcoma stem cells. In current study, EZH2 inhibitors will be employed to evaluate the importance of EZH2 in occurrence of drug resistance of CSC both in vitro and in vivo. Furthermore, we will investigate the ways through which EZH2 affect the chemotheraphy sensitivity. Finally, we will also study the signal pathways through which EZH2 mediates the expression of ABC transporter protein or apoptosis relevant proteins. This study will not only confirm the role of EZH2 in the drug resistance of osteosarcoma CSC, but also provide a potential target for osteosarcoma therapy.

骨肉瘤干细胞（Cancer Stem Cell, CSC）可能是造成骨肉瘤对化疗药物失敏感的重要原因，但相关研究甚少，其分子本质远未阐明。我们的研究发现多梳蛋白EZH2在骨肉瘤CSC中显著上调，通过抑制EZH2活性或沉默EZH2均能恢复骨肉瘤CSC对化疗药物的敏感性，提示EZH2与骨肉瘤CSC对化疗药物不敏感有关。本课题将应用小分子EZH2抑制剂作为分子探针，结合RNA干扰、免疫沉淀等分子生物学手段研究EZH2在骨肉瘤CSC中的表达及其对骨肉瘤CSC化疗药物敏感性的影响，进而研究其对ABC转运蛋白、凋亡蛋白p53及抗凋亡蛋白BCL2的调控及分子机制，以期发现EZH2介导骨肉瘤CSC化疗失敏感的主要途径、关键靶蛋白及分子网络。本研究将从肿瘤CSC这个全新的视角认识EZH2的生物学功能，揭示骨肉瘤CSC化疗失敏感的关键分子，为发展基于EZH2的骨肉瘤治疗策略提供理论依据。

骨肉瘤干细胞（Cancer Stem Cell, CSC）可能是造成骨肉瘤对化疗药物失敏感的重要原因，但相关研究甚少，其分子本质远未阐明。我们的研究发现多梳蛋白EZH2在骨肉瘤CSC中显著上调，通过抑制EZH2活性或沉默EZH2均能恢复骨肉瘤CSC对化疗药物的敏感性，提示EZH2与骨肉瘤CSC对化疗药物不敏感有关。此外，我们研究发现骨肉瘤的一线化疗药物ADR能够增强骨肉瘤肿瘤干细胞的特性，这一作用不仅与EZH2等关键因子的转录激活密切相关，还有Klf4的上调有关，因此，靶向抑制Klf4可以有效对抗ADR引起的肿瘤干细胞特性。本研究不仅从肿瘤CSC这个全新的视角认识EZH2的生物学功能，揭示了骨肉瘤CSC化疗失敏感的关键分子，还为发展基于EZH2-Klf4的骨肉瘤治疗策略提供理论依据。