酮体代谢限速酶OXCT1调控NF-κB在肺癌中的功能及其分子机制研究

Ketone bodies are produced by the liver from fatty acids, and it is an essential supplementary way of energy metabolism in human body. As a part of lipid metabolism, the function of ketone body metabolism in cancer is still unclear. Our previous study demonstrated that the expression of OXCT1 in lung cancer cells and patient’s tissue were significantly elevated compared with the normal samples. Knocking down of OXCT1 inhibited the cell proliferation and migration of lung cancer cells, and also blocked the nucleus transposition of p65 (subunit of NF-κB) from cytoplasm, which finally suppressed the activation of NF-κB signaling pathway. However, the molecular mechanism is not well understood. In this project, we will investigate the functions of OXCT1 in lung cancer development and progression, and try to explore the underlying mechanism of its action at the cellular and whole-body levels by metabolic products analysis, proteins interaction and enzyme activity assay. Completion of this project will determine the molecular mechanism of OXCT1 regulation in lung cancer growth and migration and indicate the important function played by OXCT1 in cancer metabolism. This work would also provide new information about OXCT1 as a potential anti-cancer target in lung cancer treatment.

酮体是脂肪酸氧化分解的中间产物，是人体内能量供应的重要补充。酮体代谢作为脂质代谢的重要部分，其在肿瘤中的功能目前并不明确，本课题组前期研究发现，酮体代谢限速酶OXCT1（3-oxoacid CoA-transferase 1；琥珀酰辅酶A转移酶1）蛋白表达在肺癌细胞株及病人组织样本中较正常组均明显升高，敲低OXCT1显著抑制肺癌细胞的增殖及迁移。同时，干扰OXCT1可以有效阻止核转录因子NF-κB亚基p65的入核，抑制NF-κB信号通路的激活。但具体调控的分子机制并不清楚。因此，在本项目中，我们拟通过代谢产物分析、蛋白相互作用、酶活性评价及整体动物实验等一系列研究，进一步探讨OXCT1在肺癌发生发展中的作用，并深入分析OXCT1调控NF-κB的信号转导通路。上述研究对于阐明OXCT1促进肺癌生长及迁移的分子机制，明晰酮体代谢在肿瘤代谢中的作用具有重要的意义，也为探寻肺癌治疗新靶点提供思路。

酮体，是脂肪酸氧化而产生的小分子代谢物，包括乙酰乙酸、β-羟丁酸和丙酮。癌细胞在饥饿条件下，酮体可作为支持细胞生存和增殖的替代能量来源。琥珀酰辅酶A转移酶1 （3-oxoacid CoA-transferase 1，OXCT1）是酮体分解代谢中的关键酶，其催化的反应是酮体利用中的限速反应。在这个项目中，我们发现OXCT 1通过酮体稳态调节SREBP1-TRIM21-NF-κB信号通路。其中，OXCT1可以调节β-羟丁酸（β-HB）的稳态，而β-羟丁酸可作为信号分子在非小细胞肺癌细胞中调控SREBP1的蛋白表达。进一步，SREBP1作为转录因子可以结合E3泛素连接酶TRIM21的启动子，通过转录调控TRIM21蛋白表达及其介导的NF-κB泛素化影响非小细胞肺癌的发生发展。此外，我们亦在小鼠体内及临床组织样本中验证了OXCT1对非小细胞肺癌发生发展的促进作用。