eIF4A3/circPHKB/miR-1234-3p/CYP2W1信号轴的确立及其在HCC细胞耐受索拉非尼中的意义研究

索拉非尼的治疗抵抗是晚期肝细胞癌（HCC）患者生存获益有限的重要原因，相关机制亟待深入探讨。本课题组对索拉非尼耐药HCC细胞筛选发现，环状RNA circPHKB在耐药细胞中过表达，抑制其表达可显著降低细胞的耐药性；真核翻译起始因子4A3（eIF4A3）可能是导致circPHKB表达升高的关键因子，而circPHKB可能通过吸附细胞中的miR-1234-3p，导致细胞色素P450第2家族W亚族多肽1（CYP2W1）表达升高，最终引起耐药。本项目拟以正常和耐药HCC细胞为模型，结合动物实验深入探讨：①eIF4A3/circPHKB/miR-1234-3p/CYP2W1信号轴在HCC细胞中的确立；②激活与阻断该信号轴对HCC细胞耐受索拉非尼的影响；③该信号轴激活状态与索拉非尼治疗预后的关系。通过对上述问题的探索，以期为阐明HCC细胞耐受索拉非尼的分子机理、针对性设计临床治疗策略提供科学依据。

The resistance of sorafenib is an important reason for limited survival benefits in hepatocellular carcinoma (HCC) patients, and associated mechanisms need further study. Our previous data showed that circular RNA circPHKB is overexpressed in sorafenib-resistant HCC cells. Knock-down of circPHKB significantly decreased the sorafenib resistance of HCC cells. Moreover, the eukaryotic initiation factor 4A3 (eIF4A3) may be a key factor which up-regulating circPHKB in sorafenib-resistant HCC cells. The circPHKB could further sponge miR-1234-3p and down-regulate its expression in cells. And the down-regulation of miR-1234-3p results in the overexpression of cytochrome P450 2W1 (CYP2W1) which increases the sorafenib resistance of HCC cells. Using normal HCC cells and sorafenib-resistant HCC cells as cell model, combined with animal experiments, this project will focus on several key questions as follow: ①Identification of the eIF4A3/circPHKB/miR-1234-3p/CYP2W1 signaling axis in HCC cells; ② The significance of the eIF4A3/circPHKB/miR-1234-3p/CYP2W1 signaling axis in sorafenib resistance of HCC cells; ③ The correlation of the eIF4A3/circPHKB/miR-1234-3p/CYP2W1 signaling axis activation with the prognosis of HCC patients upon sorafenib treatment. The answers of these questions will provide scientific evidence for exploring the molecular mechanisms of sorafenib resistance in HCC cells and developing new strategy to sensitize sorafenib in HCC.