Fads2调控Acat1介导脂代谢重编程促进结肠癌化疗耐药的作用及机制研究

Colon cancer is a common malignant gastrointestinal cancer. 5-FU-based chemotherapy is its main treatment, but 5-FU resistance of colon cancer is the main reason leading to its treatment failure. Our previous study found that the enhanced oxidative phosphorylation of mitochondrial fatty acids is an important metabolic feature of 5-FU resistance colon cancer cells. It was also identified that increased Fads2 expression activity of fatty acid desaturase is to promote the reprogramming of lipid metabolism in drug-resistant cells resulting in increased fatty acid oxidation , Which in turn promotes the key factors of its chemotherapy resistance. In this project, based on previous studies, using Fads2 intestinal transgenic mice and Fads2 high and low expression of colon cancer cells as a model, combined with clinical specimens and big data analysis. It was further confirmed that Fads2 transcriptionally regulates Acat1 activity by heterodimer formation with PPAR-γ, which in turn promotes the enhancement of the mitochondrial fatty acid oxidative phosphorylation in 5-F-resistant colon cancer cells. The purpose of this study was to elucidate the effect of reprogramming of lipid metabolism in colon cancer on its drug susceptibility and its action pathways, in order to select clinically predictive markers of 5-FU resistance in colon cancer and find therapeutic targets for reversing 5-FU resistance.

结肠癌是常见的恶性消化道肿瘤，以5-FU为基础的化疗是其主要的治疗手段，但结肠癌5-FU耐药是导致其治疗失败的主要原因。 本课题组前期研究发现线粒体脂肪酸氧化磷酸化增强是5-FU耐药结肠癌细胞的重要代谢特征，并鉴定出脂肪酸去饱和酶Fads2表达活性增强是促进耐药细胞脂代谢重编程导致脂肪酸氧化增强，进而促进其化疗抵抗的关键因素。本项目拟在前期研究基础上，利用Fads2肠道特异性转基因小鼠及Fads2高低表达的结肠癌细胞为模型，结合临床标本及大数据分析，进一步证实Fads2通过与PPAR-γ形成异二聚体转录调控Acat1活性，进而促进5-FU耐药结肠癌细胞线粒体脂肪酸氧化磷酸化增强的作用及分子机制。本研究旨在阐明结肠癌脂代谢重编程对其药物敏感性的影响及作用途径，以期为临床筛选出预测结肠癌5-FU耐药标志物，并寻找到逆转5-FU耐药的治疗靶点提供理论依据。

结肠癌是常见的恶性消化道肿瘤，以5-FU为基础的化疗是其主要的治疗手段，但结肠癌5-FU耐药是导致其治疗失败的主要原因。 本课题组研究发现线粒体脂肪酸氧化磷酸化增强是5-FU耐药结肠癌细胞的重要代谢特征，并鉴定出脂肪酸去饱和酶Fads2表达活性增强是促进耐药细胞脂代谢重编程导致脂肪酸氧化增强，进而促进其化疗抵抗的关键因素。本项目利用Fads2肠道特异性转基因小鼠及Fads2高低表达的结肠癌细胞为模型，结合临床标本及大数据分析，证实Fads2通过与PPAR-γ形成异二聚体转录调控Acat1活性，进而促进5-FU耐药结肠癌细胞线粒体脂肪酸氧化磷酸化增强的作用及分子机制。本研究阐明结肠癌脂代谢重编程对其药物敏感性的影响及作用途径，以期为临床筛选出预测结肠癌5-FU耐药标志物，并寻找到逆转5-FU耐药的治疗靶点提供理论依据。