TRIM25调控脂代谢重编程促进肝癌转移的机制研究

脂类代谢异常与肝癌的恶性进展密切相关，但其异常活化的机制尚未完全阐明。申请人前期工作发现TRIM25促进肝癌细胞增殖，并且肝癌组织中TRIM25高表达与肝癌患者不良预后显著相关，但其在肝癌转移中的功能及机制仍有待研究。本项目通过体外功能实验、肝癌临床标本和TCGA数据库，证实TRIM25是肝癌转移复发的重要驱动因子。RNA-seq分析提示TRIM25缺失导致脂代谢通路异常，深入研究发现TRIM25直接调控脂质合成关键转录因子SREBP1c的表达，且发现其与SREBP1c前体蛋白存在相互作用，提示TRIM25可能靶向SREBP1c前体蛋白的酶解活化。本课题拟解析TRIM25在脂代谢重编程中的作用，并阐明TRIM25调控SREBP1c蛋白表达的分子机制，通过体内外实验及临床标本揭示TRIM25-SREBP1c功能轴在肝癌恶性转化中的作用机制，为研发更有效的肝癌治疗手段提供理论基础和干预靶点。

The abnormal lipid metabolism is closely related to the malignant progression of hepatocellular carcinoma (HCC), but the mechanism of abnormal activation has not been fully elucidated. The applicant's previous work found that TRIM25 promotes the proliferation of HCC cells, and the high expression of TRIM25 was significantly related to the poor prognosis of HCC patients, but its function and mechanism in HCC metastasis remain to be studied. Recently, through in vitro function experiments, clinical specimens of HCC and TCGA public data analysis, we found that TRIM25 is an important factor driving HCC metastasis and recurrence. RNA-seq analysis suggested that the deletion of TRIM25 caused abnormal lipid metabolism pathways. In-depth research found that TRIM25 directly regulates the expression of SREBP1c, a Key Transcriptional Factor in Lipid Biosynthesis and found that it interacts with the SREBP1c precursor protein, suggesting that TRIM25 may target the SREBP1c precursor protein enzymatic hydrolysis. This project intends to analyze the role of TRIM25 in lipid metabolism reprogramming, and clarify the molecular mechanism of TRIM25 regulating the expression of SREBP1c protein, In vitro, in vivo assays and clinical specimens clarify that the function and mechanism of TRIM25-SREBP1c functional axis in the malignant transformation of HCC, to of providing the theoretical basis and intervention targets for developing more effective means of treatment of HCC.