CircBNC2/c-Myc/TXNIP轴介导的能量代谢在骨肉瘤发展中的作用和调控机制

骨肉瘤是最常见的原发恶性骨肿瘤，具有很高的复发率和致残率。Warburg效应是恶性肿瘤细胞生长、发展、转移的代谢基础，基于Warburg效应的肿瘤治疗策略前景广阔。申请人前期研究发现：葡萄糖饥饿刺激下，CircBNC2的表达量显著上调，并且能明显抑制骨肉瘤细胞的存活率、抑制Warburg效应；进一步探索后发现CircBNC2上游存在m6A修饰，在葡萄糖饥饿条件下能结合c-Myc并抑制其表达,进而促进肿瘤代谢抑制基因TXNIP的转录，最终影响下游代谢分子。由此推测，在葡萄糖饥饿刺激下，CircBNC2可能通过CircBNC2/c-Myc/TXNIP轴发挥作用，减轻Warburg效应，从而抑制骨肉瘤转移。本课题旨在从CircBNC2/c-Myc/TXNIP轴介导的能量代谢层面来揭示环状RNA调控肿瘤的新机制，同时为肿瘤相关非编码RNA研究提供新的思路，从而为骨肉瘤的治疗提供理论基础和实验依据。

Osteosarcoma is the most common primary malignant bone tumor in the world with high recurrence and disability rate. “Warburg effect” is the theory basis of tumor metabolism, relating to the growth, development, and metastasis of malignant tumor cells. The research based on the “Warburg effect” has broad prospect on the clinical development and application of multiple cancer treatment. Our previous study showed that with the stress of glucose starvation, the expression of circular RNA-CircBNC2 was significantly up-regulated, leading to a significant inhibition of the survival rate and the “Warburg effect” of osteosarcoma cells. The further mechanism study showed that there were m6A binding sites on the upstream of CircBNC2, and on the condition of glucose starvation, CircBNC2 could bind c-Myc and inhibit the c-Myc protein expression, and then promote the expression level of TXNIP, which is both a downstream target gene of CircBNC2-c-Myc binding protein and a significant tumor metabolic inhibitor gene. Therefore, we speculate that under the stimulation of glucose starvation, CircBNC2 may play a role through the CircBNC2/c-Myc/TXNIP axis to alleviate the “Warburg effect” and ultimately inhibit the metastasis of osteosarcoma. According to previous studies and in vitro and vivo experiments, the role and regulation mechanism of energy metabolism mediated by CircBNC2/c-Myc/TXNIP axis in the development of osteosarcoma will be revealed, which will simultaneously provide both theoretical basis and experimental basis for the treatment of osteosarcoma.