C/EBPα促进肝癌发生发展的机制研究及其在肝癌个体化治疗中的初步探索

Molecular targeted therapy is an important research direction to improve the prognosis of hepatocellular carcinoma (HCC) patients. Exploring new molecular target is a hotspot. Transcriptional factor C/EBPα plays an important role in pathophysiology of normal hepatocytes. Most research showed that C/EBPα was a tumor suppressor in HCC, however, some study reported that C/EBPα in some HCC patients increased not decreased and these patients had poorer prognosis. C/EBPα combined with alpha-fetoprotein (AFP) or thrombus can predict HCC prognosis. Our previous study found that C/EBPα promoted HCC through DKK4 which was a negative regulator of Wnt signaling pathway. Therefore, the aim of this project is to investigate the mechanism and downstream signaling pathway difference between HCC patients with high or low C/EBPα expression. Moreover, we will verify that C/EBPα promotes HCC progress by negative regulating DKK4 and then affecting Wnt/β-catenin signaling pathway in clinical samples and in vitro. Finally, we will explore and evaluate the therapeutic effect of C/EBPα on HCC proliferation and migration in nude mouse liver cancer model, which is supposed to supply information for clinical treatment in future.

肝细胞肝癌（HCC）的分子靶向治疗是目前临床改善患者预后的重要研究方向，新的分子靶点的探索是研究热点。转录因子C/EBPα在肝细胞正常生理病理过程中均发挥重要作用。多数肝癌的研究显示C/EBPα是肿瘤抑制因子，但也有报道部分肝癌患者C/EBPα表达水平不降反升，并且这部分患者的预后更差，C/EBPα联合甲胎蛋白（AFP）或血管中有无癌栓等临床信息能预测预后状态。工作基础发现C/EBPα促进肝癌进展可能通过Wnt通路负调控因子DKK4发挥作用，因此本研究拟首先在肝癌患者中按照C/EBPα表达高低，分别研究C/EBPα在肝癌的作用机制及其下游信号通路的差别，并在临床样本和体外功能实验中验证C/EBPα高表达肝癌细胞系负调控DKK4改变下游Wnt/β-catenin通路促进肝癌发展。进一步在裸鼠肝癌模型中初步探索和评估C/EBPα作为治疗靶点干预肝癌增殖转移的治疗效果，为今后的临床应用提供线索。

C/EBPa目前是肝癌治疗的一个重要靶点，本研究发现在部分肝癌患者中C/EBPa表达升高，体外研究发现降低表达肝癌细胞株HepG2和Huh7细胞的C/EBPa，细胞增殖能力显著降低；裸鼠原位肝癌模型实验证实Huh7细胞降低表达C/EBPa后体内成瘤能力显著降低；C/EBPa降低表达后IGFBP1、DcR3表达明显减少，荧光素酶实验显示C/EBPa调控IGFBP1、DcR3的转录表达，而DcR3在肝纤维化、肝硬化患者中表达升高，对肝硬化有较高的诊断价值，以上提示降低表达C/EBPa抑制肝癌的增殖，该作用可能通过下调IGFBP1和DcR3实现。