PGC1A/THRB信号诱导的线粒体融合在肾透明细胞癌脂质代谢中的作用和机制研究

One of the most prominent features of renal clear cell carcinoma (ccRCC) is abnormal lipid metabolism. There is no systematic study on the mechanism and biological significance of ccRCC lipid metabolism abnormalities. Previous study of the applicant revealed that the expression of key molecules (PGC1A and UCP1) and mitochondrial fusion-related genes (MFN2 and OPA1) of the lipid browning depletion pathway was decreased in TCGA database of ccRCC, the number and morphology of mitochondria were abnormal by transmission electron microscopy. Further studies have found that overexpression of PGC1A promotes UCP1 expression can eliminate lipid accumulation and inhibit tumor growth, but the mechanism remains unclear. This project studied the relationship between lipid browning and organ-related functional genes with ccRCC disease stage and survival time. We proposed and verified the scientific hypothesis that PGC1A acts as a coactivator to restore mitochondrial function by binding to transcription factor (Thyroid hormone receptor β, THRB)-mediated mitochondrial fusion and to increase UCP1 expression for lipid browning by cellular molecular biology and animal model. The results of this project will help to understand the role and mechanism of mitochondrial fusion and lipid browning in lipid metabolism of ccRCC, and provide new therapeutic strategies and targets for the treatment of ccRCC.

脂质代谢异常是肾透明细胞癌（ccRCC）为最为显著的特征之一，目前对ccRCC脂质代谢异常的发生机制及生物学意义尚缺乏系统研究。申请者前期通过TCGA数据库分析发现ccRCC中脂质棕色化消耗脂质途径的关键分子（PGC1A和UCP1）以及线粒体融合相关基因（MFN2和OPA1）表达降低，电镜检测发现线粒体数量形态明显异常。进一步发现PGC1A促进UCP1表达可以消除脂质堆积，抑制肿瘤生长，但具体机制尚未研究。本课题从ccRCC脂质代谢的临床意义入手，研究脂质棕色化及线粒体融合与ccRCC的关系，通过细胞分子生物学、动物模型等研究方法，提出并验证PGC1A作为辅助激活因子结合转录因子（甲状腺激素受体，THRB）介导线粒体融合恢复线粒体功能及增加UCP1表达促进脂质棕色化的科学假说。研究结果将有助于了解线粒体与脂质棕色化在ccRCC脂质代谢中的作用和机制，并为治疗ccRCC提供新的策略和靶点。

本研究系统的探索并分析了肾透明细胞癌中包括现ccRCC中脂质棕色化消耗脂质途径的关键分子（PGC1A和UCP1）,THRB以及线粒体融合相关基因（MFN2和OPA1）的表达以及相关性分析，电镜检测线粒体数量形态和数量明显异常。通过实验发现PGC1A/THRB促进UCP1,MFN2和OPA1表达可以消除脂质堆积，抑制肿瘤生长。本课题研究脂质棕色化及线粒体融合与ccRCC的关系，通过细胞分子生物学、动物模型等研究方法，验证PGC1A作为辅助激活因子结合转录因子（甲状腺激素受体，THRB）介导线粒体融合恢复线粒体功能及增加UCP1表达促进脂质棕色化的科学假说。研究结果将有助于了解线粒体与脂质棕色化在ccRCC脂质代谢中的作用和机制，并为治疗ccRCC提供新的策略和靶点。