转移是导致肝癌死亡率高的主要原因，FOX转录因子在其中发挥重要调节作用，然而分子机制不明。我们率先发现：①FOXE3在肝癌中表达显著低于癌旁和正常肝组织，FOXE3低表达患者复发率高生存率低，与肝癌预后不良密切相关；②下调FOXE3促进肝癌侵袭和转移，上调FOXE3抑制肝癌侵袭和转移；③CHD4/NuRD复合物抑制FOXE3转录。据此推测：CHD4/NuRD通过与FOXE3启动子结合抑制其表达，被FOXE3转录抑制的直接调控靶基因由此解除抑制导致表达上调，从而促进肝癌侵袭和转移。然而，FOXE3抑制肝癌转移的分子机制是什么？CHD4/NuRD如何抑制FOXE3表达？干预CHD4/NuRD-FOXE3途径能否有效抑制肝癌转移？本课题拟通过细胞、裸鼠、条件敲除鼠、临床组织标本等一系列实验阐明以上三个问题。研究结果不仅有望拓展对FOXE3功能的新认识，而且为肝癌治疗提供新的切入点和思路。

Recurrence and metastasis remain the most common causes of lethal outcomes in hepatocellular carcinoma (HCC) after curative resection. Thus it is critical to discover the mechanisms underlying HCC metastasis. Forkhead box (Fox) proteins are a family of evolutionarily conserved transcriptional regulators that play important roles in both normal biological processes and in cancer development. Previously, we discovered that: ①FOXE3 expression was markedly lower in HCC tissues than in adjacent noncancerous tissues and normal liver tissues. HCC patients with low expression of FOXE3 had shorter overall survival and higher recurrence rates than those with high expression of FOXE3. ②Knockdown of FOXE3 significantly increased the migration, invasion, and lung metastasis of HCC cells, whereas over-expression of FOXE3 decreased these processes. ③CHD4/NuRD complex inhibited FOXE3 transcription. Based on these studies, we hypothesize that CHD4/NuRD directly binds to the promoter of FOXE3 and inhibits its expression. FOXE3 inhibition reactivates FOXE3 target genes’ expression, thereby leading to the invasion and metastasis of HCC. However, what is the molecular mechanism of FOXE3-mediated HCC metastasis? How CHD4/NuRD complex inhibits FOXE3 transcription? Does inhibition of CHD4/NuRD-FOXE3 pathway decrease HCC metastasis? In this project, we are going to answer these important questions. We are going to use cell lines, nude mouse model, conditional knockout mouse model, and human HCC samples to study these questions. These studies not only discover the new function of FOXE3, but also provide potential a candidate biomarker for HCC prognosis and a target for new therapies.