MicroRNA-30a通过自噬相关信号通路调控骨肉瘤耐药的分子机制研究

Osteosarcoma is the most common malignant primary bone tumor，unfortunately, treatment failures are usual due to the chemoresistance.Our recent study published on Cancer Research and Autophagy demonstrated that Beclin1 as an autophagy related protein played an important role in autophagy and drug resistance in osteosarcoma.Our further experiments also showed that MicroRNA-30a inhibited Beclin1's expression in dose dependence.As Beclin1 is an important autophagy related protein and closely associated with apoptosis，we hypothesized that miR-30a regulates drug resistance through Beclin1 related autophagy signal pathways in osteosarcoma.We will sequentially expand above findings by exploring how miRNA-30a affects autophagy related signal pathways and drug resistance through Beclin1 and Beclin1 and its compounds in osteosarcoma. This project will provide novel potential targets for the treatment of osteosarcoma.

骨肉瘤是临床上最多见的原发性恶性骨肿瘤，化疗药物耐药性的形成是其治疗失败的常见原因。项目组最近在《Cancer Rearch》和《Autophagy》上发表论文报道了高迁移率族蛋白1通过与Beclin1自噬相关蛋白结合参与了骨肉瘤细胞自噬和化疗药物耐药性形成。在进一步的实验中我们发现MicroRNA-30a与Beclin1在骨肉瘤化疗中有明显的量效关系。鉴于Beclin1是重要的自噬通路蛋白，而且自噬与凋亡紧密相关，申请者提出miRNA-30a调控Beclin1自噬信号通路，进而影响骨肉瘤细胞耐药形成的假说。针对上述假说，本项目拟采用各种先进的研究方法和技术手段，深入探讨miRNA-30a如何通过调控Beclin1及其复合物的表达进而影响骨肉瘤细胞自噬通路和耐药性的分子机制。开展本项目可望揭示miRNA-30a在细胞自噬作用中的新机制，为对抗骨肉瘤的靶向治疗和药物开发提供新的思路。

骨肉瘤是临床上最多见的原发性恶性骨肿瘤，化疗药物耐药的形成是其治疗失败的常见原因。项目组采用各种先进的研究方法和技术手段，初步阐明了miRNA-30a正向调节Beclin1自噬信号通路，通过增加骨肉瘤细胞自噬，减少凋亡，进而提高骨肉瘤细胞的化疗药物敏感性的机制。同时发现KLF4通过结合HMGB1启动子增加HMGB1的表达，诱导化疗药物耐药。而在化疗药物治疗中，未折叠蛋白反应（UPG）激活NF-κB通路发挥细胞保护作用。本项目的完成可望为对抗骨肉瘤的靶向治疗和药物开发提供新的思路。