circXPO6抑制c-Myc蛋白泛素化降解促进三阴性乳腺癌发生和进展的作用及机制研究

三阴性乳腺癌（TNBC）预后差，目前尚无有效的治疗手段。研究表明有氧糖酵解（Warburg效应）参与TNBC发生及进展，c-Myc参与调控Warburg效应，但c-Myc上游调节因子尚未明确。我们创新性地通过c-Myc的RIP-Seq实验逆向寻找到其上游circXPO6，并证实circXPO6与TNBC的发生及进展相关，机制研究初步发现circXPO6结合c-Myc蛋白后抑制其泛素化降解，使得c-Myc含量增加，促进TNBC由氧化磷酸化转向有氧糖酵解，但具体机制不清楚。由此，我们提出circXPO6抑制c-Myc蛋白泛素化降解调控Warburg效应促进TNBC的发生发展及转移，拟结合动物实验和临床研究并综合运用分子生物学、生物信息学等多种技术探讨circXPO6如何调控c-Myc参与TNBC发生及进展。本项目不仅阐明TNBC发生发展及转移的机制，而且可为TNBC的诊疗提供新靶点和新思路。

Triple negative breast cancer (TNBC) is associated with poor prognosis but limited effective treatment options. Previous studies have shown that c-Myc is involved in the carcinogenesis and progression of breast cancer by regulating aerobic glycolysis (the Warburg effect). However, the upstream regulators have not been clarified. Through RIP-seq experiment of c-Myc, we creatively identified the upstream regulator circXPO6, and confirmed that circXPO6 is related to the carcinogenesis and progression of TNBC. The preliminary study found that circXPO6 can bind to c-Myc protein and then inhibit its ubiquitin-mediated degradation, resulting in the metabolism switch from oxidative phosphorylation to aerobic glycolysis in TNBC cells by raised level of c-Myc. However, the detailed mechanism remains unclear. Therefore, we proposed the hypothesis that circXPO6 can regulate the Warburg effect by inhibiting the ubiquitin-mediated degradation of c-Myc, leading to TNBC carcinogenesis, progression and metastasis. We intend to integrate animal research with clinical research, and comprehensively apply the techniques of molecular biology and bioinformatics to further discuss how circXPO6 regulates c-Myc in TNBC carcinogenesis and progression. Our project not only clarify the mechanism of TNBC carcinogenesis, progression and metastasis, but also offer potential therapeutic targets and new strategies in the diagnosis and treatment of TNBC.