MICAL2介导HIF-1α的氧化修饰增强嘌呤合成促进三阴性乳腺癌生长

低氧是肿瘤微环境的常见特征，但乳腺癌中低氧诱导因子HIF-1α的表达调控和功能机制仍未完全阐明。本项目前期研究显示，相比其他分型，低氧上调三阴性乳腺癌（TNBC）细胞中HIF-1α蛋白表达；HIF-1α促进TNBC细胞在低氧条件下生长；蛋白质修饰组学分析发现低氧诱导TNBC细胞中HIF-1α甲硫氨酸氧化修饰，证实MICAL2促进低氧条件下HIF-1α稳定；转录组测序和代谢组检测提示低氧条件下HIF-1α增强TNBC细胞嘌呤合成。本项目拟首先通过体内外实验结合临床样本分析进一步证实低氧条件下HIF-1α甲硫氨酸氧化修饰增加其稳定性促进TNBC生长；其次，明确MICAL2介导HIF-1α甲硫氨酸氧化修饰位点，证明其在稳定HIF-1α蛋白中的作用及机制；最后，解析HIF-1α通过转录调控PPAT以增强嘌呤合成。该项目的完成将为TNBC中HIF-1α调控机制研究及依此开发新治疗策略提供新理论依据。

Hypoxia is a common feature of tumor microenvironment, but the expression regulation and functional mechanism of HIF-1α in breast cancer have not been fully elucidated. Previous studies of this project showed that hypoxia upregulated the expression of HIF-1α protein in TNBC cells compared with other subtypes. HIF-1α promoted the growth of TNBC cells under hypoxia. Proteomics analysis showed that hypoxia induced the oxidative modification of HIF-1α methionine in TNBC cells, which confirmed that MICAL2 promoted the stability of HIF-1α under hypoxia. Transcriptome sequencing and metabonomics detection showed that MICAL2 promoted the stability of HIF-1α under hypoxia HIF-1α enhanced purine synthesis in TNBC cells under hypoxia. This project intends to further confirm that HIF-1α methionine oxidative modification increases its stability and promotes the growth of TNBC under hypoxic conditions through in vitro and in vivo experiments and clinical sample analysis. Secondly, to identify MICAL2 mediated HIF-1α methionine oxidative modification site and prove its role and mechanism in stabilizing HIF-1α protein. Finally, to analyze HIF-1α through transcriptional regulation of PPAT to enhance purine synthesis . The completion of this project will provide a new theoretical basis for the research on the regulatory mechanism of HIF-1α in TNBC and the development of new therapeutic strategies.