高尔基体蛋白GOLM1感受胆固醇变化调控肝癌RTKs选择性自噬的机制及干预研究

高尔基体改变在肝癌演进中扮演了重要角色,其中高尔基体关键蛋白GOLM1调控受体酪氨酸激酶（RTKs）活化是关键驱动因素。但是“GOLM1-RTKs功能轴”的上游活化因素仍不清楚。我们近期研究发现，胆固醇代谢水平变化上调GOLM1的同时能促进RTKs活化，抑制GOLM1显著拮抗胆固醇引起的RTKs活化细胞表型；进一步研究发现GOLM1调控RTKs选择性自噬是胆固醇代谢促进RTKs活化的重要机制。本项目以“胆固醇上调GOLM1调控RTKs选择性自噬活化”为研究主线，重点开展以下研究：1）阐明GOLM1调控RTKs选择性自噬促进活化的分子机制；2）探索胆固醇代谢上调高尔基体蛋白GOLM1的上游调控机制；3）分析干预胆固醇代谢途径对提高肝癌靶向药物敏感性的研究，探索其在提高肝癌靶向治疗疗效中的潜在临床应用前景。为深入研究高尔基体感受代谢变化调控RTKs选择性自噬的机制及其临床干预价值提供实验依据。

Golgi changes play a key role in the progression of liver cancer. GOLM1, a key Golgi protein, which regulates the activation of receptor tyrosine kinase (RTKs) is the key driver of liver cancer metastasis. However, the upstream activation factors and molecular mechanism of “GOLM1-RTKs” axis is still largely unknow. In our previous studies, we found that cholesterol metabolism could significantly upregulate GOLM1 levels as well as activation of RTKs. Inhibiting of GOLM1 could significantly antagonize the cell phenotype of cholesterol metabolism in promoting the activation of RTKs. In depth studies found that GOLM1 regulation of selective autophagy of RTKs is an important mechanism of cholesterol metabolism in promoting the activation of RTKs. This project takes "cholesterol up regulating GOLM1 to regulate RTKs selective autophagy in promote RTKs activation" as the main research line, focusing on the following study: 1) clarifying the molecular mechanism of GOLM1 in regulating RTK selective autophagy and promote its activation; 2) exploring the upstream regulatory mechanism of cholesterol in upregulating of GOLM1 ; 3) to investigate whether targeting the cholesterol metabolism pathway could improve the drug sensitivity of liver cancer. It provides important experimental basis and potential clinical value for further study of the mechanism of Golgi response to metabolic changes regulating RTKs selective autophagy and intervention in liver cancer.