hsa_circ_0046264/miR-4763-3p/miR-583/GPX4信号轴对骨肉瘤铁死亡的调控作用及机制研究

铁死亡是一种铁依赖的非凋亡性细胞死亡形式，在肿瘤发生、耐药中起重要作用，circRNA参与骨肉瘤多种生物学过程，但circRNA在骨肉瘤中对铁死亡的调控尚未报道。申请人前期筛选出circ_0046264在骨肉瘤组织中高表达，且与临床复发和预后差相关；生物信息学预测和体外实验表明，circ_0046264可能通过调控miR-4763-3p/miR-583/GPX4轴进而调控骨肉瘤细胞铁死亡。本项目将在前期研究基础上，扩大临床样本量，进一步明确circ_0046264与临床预后的关系；并基于骨肉瘤细胞系干预circ_0046264，阐明其对骨肉瘤细胞铁死亡的影响及具体机制；最后，拟建立circ_0046264稳定敲低骨肉瘤细胞系，并利用裸鼠成瘤实验探究干预circ_0046264对骨肉瘤生长的影响。本项目将首次探究circRNA在骨肉瘤中调控铁死亡的作用，为骨肉瘤治疗提供潜在的新靶点和新思路。

Ferroptosis is an iron-dependent and non-apoptotic form of cell death, which plays an important role in tumorigenesis and recurrence. circRNA is involved in various biological processes of osteosarcoma, but no circRNA has been reported to regulate ferroptosis in osteosarcoma. We previously screened out a highly expressed circRNA (circ_0046264) in the osteosarcoma tissues, which was related to recurrence and poor prognosis of patients; bioinformatics predictions and in vitro experiments showed that circ_0046264 may regulate ferroptosis in osteosarcoma via miR-4763-3p/miR-583/GPX4 axis. Based on the preliminary research, this project plan to analyze more osteosarcoma patients to further clarify the relationship between circ_0046264 and clinical prognosis; to investigate the effects of circ_0046264 on ferroptosis and its mechanism based on circ_0046264 interventional experiments in osteosarcoma cell lines; to explore the effect of intervention circ_0046264 on the growth of osteosarcoma via nude mouse tumor formation experiment. This project will explore the role of circRNA in regulating ferroptosis in osteosarcoma for the first time, and will provide potential new targets and new insights for the treatment of osteosarcoma.