VCP/p97-20S蛋白酶体调控肝癌复发的分子机制及其临床应用

肝癌复发是影响肝癌预后和生存率的重要因素，也是肝癌治疗的主要困扰和瓶颈。一般认为，肝癌复发主要与肿瘤因素有关，而对于肝脏自身状态在复发过程中的改变及其对复发的影响，目前研究甚少。我们的前期工作发现，在肝癌复发病人的远癌组织中VCP/p97和20S蛋白酶体稳定、统一的上调，而19S蛋白酶体则没有明显变化；更深入的研究揭示了VCP-20S蛋白酶体的存在以及20S蛋白酶体活性的上升，同时还观察到肝脏代谢模式的明显转换。由此推测，在复发远癌中可能形成一种非经典的VCP-20S蛋白酶体，通过重塑肝脏的代谢模式协助肝癌复发。在本项目中，将进一步通过分子、细胞、动物和临床病人等多个水平研究，阐明VCP-20S蛋白酶体通过选择性降解特异底物蛋白，重塑肝脏的蛋白质稳态和代谢模式导致肝癌复发的分子机制；并开发基于20S蛋白酶体活性的光声成像纳米探针及超声检测平台，推进肝癌复发的早期预测、预防和精准医疗。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with the highest number of deaths worldwide. Recurrence of HCC is the long-lasting harassment and major bottleneck in the treatment of HCC, which drastically affects the prognosis and survival rate of HCC patients. Thus, the discovery of new molecular markers is crucial for the prediction, early diagnosis and precise treatment of HCC recurrence. In the preliminary work, we have used an iTRAQ-based proteomics approach to screen for protein biomarkers associated with HCC recurrence. The results show that the stably up-regulation of the proteasome 20S complex and VCP/p97 in the distant tumor tissue of HCC recurrence patients, together with the dysregulation of a great number of key metabolic enzymes in the liver, especially those in glucose and lipid metabolism，indicating there is remarkable remodeling of hepatic metabolic pattern during HCC recurrence. In this project, these important protein markers of HCC recurrence will be further confirmed in large cohort recurrence/non-recurrence patients and by the TCGA analysis. Multi-layer studies including molecular level, cell and animal models will be employed to elucidate the molecular mechanism of how the VCP/p97-20S proteasome remodels the protein homeostasis and the hepatic metabolism by selective degradation of its specific substrate proteins, and finally leads to the HCC recurrence. This study will also develop Nano-probe and corresponding ultrasonic detection platform based on the activity of 20S proteasome to promote the early prediction, prevention and precise treatment of HCC recurrence.