CD47调控肝细胞癌氧化还原状态的分子机制及靶向应用探索

肝细胞癌（HCC）是我国常见的恶性肿瘤之一，在HCC发展过程中，需克服氧化应激带来的不良影响。我们前期的工作发现CD47在HCC中有较高的表达水平，可促进Nrf2及其下游抗氧化基因的表达进而帮助细胞抵抗氧化应激，但具体机制尚不清楚。通过分析发现CD47可促进HCC中mTORC1信号通路的活性，而mTORC1可稳定Nrf2的表达。此外，CD47抗体可引起HCC内活性氧（ROS）水平的升高。根据前述工作基础，我们提出“CD47通过mTORC1-Nrf2信号通路帮助HCC抵抗氧化应激”的假说。为证实该假说并将此机制应用于HCC的靶向治疗，本项目拟研究：1.CD47促进mTORC1信号通路活性进而上调抗氧化基因表达的机制；2.CD47抗体升高HCC的ROS水平，提高HCC对化疗药物敏感性的应用；3.评价靶向CD47的纳米复合材料控制性释放ROS杀伤HCC的治疗价值，为HCC的靶向治疗提供新的方式。

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, HCC must overcome the adverse effects of oxidative stress in their development. Our previous data indicated that the expression level of CD47 was relative high on HCC specimens and CD47 could help HCC resist oxidative stress by elevating the expression of Nrf2 and its downstream antioxidant genes, but the mechanism is not clear. By signal pathway analysis we found CD47 could promote the activity of mTORC1 signaling pathway in HCC and mTORC1 could stabilize Nrf2 expression. In addition, CD47 antibody could increase the ROS level in HCC. Based on the above work, we proposed the hypothesis that CD47 helped HCC resist oxidative stress through mTORC1-Nrf2 signaling pathway. In order to confirm the hypothesis and apply it to targeted therapy of HCC, this project intends to study: 1. The mechanism of CD47 promoting the activity of mTORC1 signaling pathway and then upregulating the expression of antioxidant genes. 2. The application of CD47 antibody increasing ROS level and chemosensitivity in HCC. 3. The therapeutic value of targeted CD47 nanocomposites for controlled release of ROS to kill HCC, providing a new way for targeted therapy of HCC.