FGF19-FGFR4信号激活FOXD1表达及其在促进肝癌转移中的作用

Metastasis account for the great majority of hepatocellular carcinoma-associated deaths. Therefore, it is critical to discover the mechanisms underlying HCC metastasis. Forkhead box (FOX) transcription factors are evolutionarily conserved regulators with a central role not only in normal biological processes, but also in cancer development. Previously, we discovered that: ①FOXD1 expression was significantly increased in HCC tissues than in adjacent noncancerous tissues and normal liver tissues. HCC patients with high expression of FOXD1 had shorter overall survival of higher recurrence rates than those with low expression of FOXD1. ②FOXD1 depletion significantly decreased invasion and migration of HCC cells, whereas FOXD1 overexpression increased these processes. ③FOXD1 transcriptional activated FGFR4 expression. FGF19 treatment, ligand of FGFR4, increased the expression of FOXD1. Based on these results, we hypothesize that FGF19-FGFR4-FOXD1 positive feedback loop may play important role in invasion and migration of HCC. However, the molecular mechanisms of FOXD1-mediated HCC metastasis and FGF19-FGFR4-regulated FOXD1 expression are still unknown. Do inhibition of FGF19-FGFR4-FOXD1 pathway decrease HCC metastasis? In this project, these important questions will be explored by using HCC cell lines, nude mouse model, conditional knockout mouse model and human HCC samples. These studies will not only discover the function of FOXD1, but also provide potential candidate marker for HCC prognosis and target for HCC therapies.

转移是导致肝癌复发和死亡率高的主要原因。FOX转录因子在其中发挥重要的调节作用，然机制不明。我们率先发现：①FOXD1在肝癌中高表达，其表达与脉管侵袭、TNM分期、远处转移正相关，FOXD1高表达患者复发率高生存率低；②上调FOXD1促进肝癌侵袭转移，下调FOXD1抑制肝癌侵袭转移；③FOXD1转录激活FGFR4表达，FGF19-FGFR4信号激活FOXD1表达。提示：FOXD1促进肝癌侵袭转移；肝癌中存在FGF19-FGFR4-FOXD1正反馈环路。然而，FOXD1促进肝癌转移的机制是什么？FGF19-FGFR4如何调控FOXD1表达？FGF19-FGFR4-FOXD1正反馈环路在肝癌进展中的作用是什么？本课题拟在前期工作的基础上，通过细胞、裸鼠、条件敲除小鼠、临床标本检测等实验，阐明上述三个问题。研究结果有望为肝癌治疗提供新的靶点和思路。

转移是导致肝癌复发和死亡率高的主要原因。转录因子的异常激活并结合到基因启动子区域在转录水平激活癌基因表达，在调节肝癌转移的过程中发挥着关键的调控作用。关键转录因子FOXD1, ETV5, ETV1, TBX19, ONECTU2, HIF1α是众多器官系统的发育中的多种细胞程序的关键调节因子，既为早期细胞命运决定所必需，又在分化和器官发生中发挥着重要作用。作为调节细胞命运的重要基因，一旦表达失常将改变细胞命运甚至癌变。本项目解析以FOXD1, ETV5, ETV1, TBX19, ONECTU2, HIF1α为关键节点的上下游生长因子信号调控网络在促进肝癌转移中的不同作用和机制。关键发现如下：（1）阐明FGF19-FGFR4信号通路通过肿瘤免疫逃逸促进肝癌转移的机制，提出FGFR4抑制剂BLU-554联合anti-PD-L1的联合免疫治疗策略可有效抑制肝癌转移。（2）阐明以ETV1为关键节点的生长因子正反馈途径在促进肝癌转移中的关键作用，为治疗ETV1介导的肝癌转移提供了新的联合抑制剂干预策略。（3）阐明TBX19与表皮生长因子EGF/EGFR形成的正反馈途径促进肝癌转移，提出EGFR抑制剂Erlotinib与RAC1抑制剂NSC23766两药联用抑制肝癌转移的策略。（4）阐明以ONECTU2为关键节点的成纤维细胞生长因子正反馈途径在促进肝癌转移中的作用，为治疗ONECUT2介导的肝癌转移提供了一种新的联合抑制剂干预策略。（5）细胞因子IL-1β诱导转录因子HIF1α异常高表达，通过重塑抑制性免疫微环境促进肝癌转移。（6）FGF19-FGFR4信号激活FOXD1表达从而促进肝癌转移。