Ras相关C3肉毒杆菌毒素底物1（RAC1）通过FBP1介导的糖代谢重构影响肝癌放疗敏感性的机制研究

肝癌放疗客观反应率较低，阻碍生存率的进一步提高，放疗抵抗发生的具体分子机制尚需探索。申请人前期利用肝癌新辅助放疗患者的血浆行基因测序和定量分析发现RAC1的高表达与放疗抵抗相关，初步的机制探究发现RAC1可以和糖异生途径关键酶FBP1发生互相作用，并诱导肝癌细胞发生糖代谢重构。我们推测放疗时，RAC1可通过磷酸化FBP1并抑制其代谢活性，从而增强糖酵解途径导致肝癌放疗抵抗。以此为基础，本项目拟1）验证RAC1高表达对肝癌细胞放疗敏感性的影响；2）解析RAC1与FBP1相互作用的具体分子机制及结合位点；3）探索靶向RAC1改善肝癌放疗敏感性的可能性。本项目有望为临床患者个体化治疗提供潜在靶点。

The objective response rate(ORR) of radiotherapy for hepatocellular carcimoma(HCC) is still low, which limited the survival benefit of radiotherapy. Therefore, the molecular mechanism of radio-resistance needs further investigation. We previously confirmed that RAC1(Ras-related C3 botulinum toxin substrate 1) was related to radio-resistance of HCC by analyzing the patients' plasma who received neoadjuvant radiotherapy, using gene deep sequencing and quantitative analysis. Preliminary research revealed that RAC1 could interact with FBP1(Fructose-1,6-bisphosphatase 1, FBP1), a key regulator in the process of gluconeogenesis, and induce glucose metabolic reprogramming. Therefore, we assume that RAC1 may induce radio-resistance of HCC by phosphorylating and inhibiting FBP1, as well as enhancing glycolysis. Based on previous findings, we will 1) verify the impact of RAC1-overexpression on the radio-sensitivity of HCC; 2) investigate the molecular mechanism and binding site of RAC1 interacting with FBP1; 3) explore the possibility of inhibiting RAC1 to improve radio-sensitivity of HCC. Our project may provide potential therapeutic targets for HCC patients according to individual characteristics.