肝细胞核因子4α对肝癌转移的调控及临床相关研究

项目名称： 肝细胞核因子4α对肝癌转移的调控及临床相关研究

项目编号： No.81201938

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 宁北芳

作者单位： 中国人民解放军第二军医大学

项目金额： 24万元

中文摘要： 肝细胞核因子4α（HNF4α）是一个肝细胞高表达的转录因子，对肝细胞功能和上皮表型的维持非常重要。我们前期报道了HNF4α可诱导肝癌细胞向肝细胞分化并抑制实验性大鼠肝癌发生，但HNF4α在肝癌转移中的作用目前尚无报道。通过比较60例肝癌临床样本中HNF4α的表达我们发现，肝癌转移灶中HNF4α表达明显低于原发灶，且HNF4a表达低的病人预后可能更差。体外研究的预实验结果显示，HNF4α可以抑制肝癌细胞的粘附、迁移和侵袭能力。前期还发现HNF4α可以抑制肝癌细胞中与肿瘤转移密切相关的NF-κB信号通路，但具体机制尚不清楚。本项目将利用可视化肝癌转移活体成像系统和经典的信号转导研究技术，深入研究HNF4α调控EMT和NF-κB的分子机制，探讨HNF4α体内抑制肝癌转移的效果和作为治疗靶点的可行性。通过分析300例以上肝癌样本中HNF4α表达和患者预后的相关性，力争为肝癌预后判断提供新的标志物。

中文关键词： 肝癌；转移；肝细胞核因子4a；RelA；预后

英文摘要： Hepatocyte nuclear factor 4α(HNF4α) is a transcriptional factor enriched in hepatocyte,which is critical for the maintenance of hepatocyte function and epithelial phenotype. We have previously reported that HNF4α could induce the differentiation of hepatoma cells to hepatocytes and suppress DEN-induced hepatocarcinogenesis. Analysis of HNF4α expression in 60 HCC cases suggested that the expression of HNF4α was significantly low in metastatic HCC lesions compared with that in primary lesions, and patients with low HNF4α expression suffered from poor prognosis. HNF4α is able to inhibit the adhesion, metastasis and invasion potential of HCC cells in vitro. Previous studies also suggested that HNF4α inhibited NF-κB signaling pathway of HCC cells, which is closely associated with cancer metastasis. In this project, visualized HCC metastasis model and classic approaches of signaling transduction research will be used to investigate the effect of HNF4α on HCC metastasis, NF-κB signaling and EMT. A large cohort of more than 300 HCC cases will be analyzed for the correlation of HNF4α expression of hepatoma and the prognosis of patients, leading to a new biomarker for HCC prognosis and therapy.

英文关键词： Hepatocellular carcinoma；Metastasis；Hepatocyte nuclear factor 4α；RelA；prognosis