GO纳米片通过HspB8-BAG3-Hsp70复合体介导MYLK4/EGFR信号通路光热抗骨肉瘤的机制研究

骨肉瘤切除后的骨缺损和肿瘤复发是目前医学治疗的难点。光热应激可使肿瘤内的热休克蛋白复合体HSPB8-BAG3-HSP70形成而产生细胞保护机制，使得光热治疗效果降低，本课题组前期研究证实氧化石墨烯（GO纳米片）修饰的复合生物支架具有良好的光热抗肿瘤功能。目前尚无“生物材料光热抗骨肉瘤的HSPB8-BAG3-HSP70复合体形成”的相关报道。本课题拟设计合成一种新型负载BAG3-shRNA的介孔纳米硅粒子与GO纳米片共同构建复合支架，通过释放shRNA下调BAG3表达而抑制HSPB8-BAG3-HSP70复合体形成以增加肿瘤对GO修饰的复合支架光热治疗的敏感性，探索光热抗骨肉瘤中的HSPB8-BAG3-HSP70通过MYLK4/EGFR介导的细胞保护机制。本课题为同时实现骨肉瘤的局部治疗及术后骨缺损的修复，避免因化疗耐药和肿瘤复发而引起的治疗失败，为提高骨肉瘤整体疗效提供新方法和新思路。

Bone defect and tumor recurrence of osteosarcoma are the current difficult problems in medicine. Our previous research demonstrated that the GO modified composite scaffold has good photothermal anti-tumor and bone regenerative capabilities. Thermal stress can increase the expression of heat shock proteins (HSPs) in cancer cells and the formation of HSPB8-BAG3-HSP70 complex, which can reduce he photothermal therapy effect as a cytoprotective mechanism. Studies on "HSPB8-BAG3-HSP70 complex formation in photothermal anti-tumor" have not been reported yet. This study intends to construct a 3D printed gene-tissue engineering composite scaffold for the prevention of bone tumor and bone defect repair by combining the mesoporous nano silicon particles loaded with BAG3-shRNA and GO nanosheets. Down-regulating the expression of BAG3 by releasing shRNA, MYLK4/EGFR pathways to inhibit the formation of the HSPB8-BAG3-HSP70 complex, for increasing the therapeutic effect of the GO modified composite scaffold. In order to suppress the bone tumor, repair the postoperative bone defect, and avoid the treatment failure and tumor recurrence caused by chemotherapy resistance, this research project intends to provide new methods and perspectives for improving the overall curative effect of osteosarcoma.