Wnt信号受体Frizzled-10对肝癌转移的调控及临床相关研究

Recurrence and metastasis of liver cancer is a major bottleneck problem in postoperative treatment, and metastasis causes up to 90% of tumor deaths.In the preliminary work, we accurately selected multiple liver cancer samples for whole genome sequencing, with the help of bioinformatics analysis and functional verification the significant overexpression gene frizzled-10 (FZD10) of intrahepatic metastatic liver cancer was screened. FZD10 is a receptor of Wnt signaling pathway and can be modulated Nodules tumor proliferation, epithelial mesenchymal transformation and stem cell characteristics, while whether FZD10 plays a role in the process of liver cancer intrahepatic metastasis has not been reported. Based on our previous work, this project intends to systematically study the regulatory effect of FZD10 on the metastasis of liver cancer cells through in vitro cell experiments and in vivo imaging models by using the liver cancer cell lines with high and low expression of FZD10.The activation effect and target of FZD10 on Wnt / β-catenin signal pathway were clarified, and the molecular mechanism of FZD10 in regulating liver cancer cell metastasis was clarified. To further explore the potential value of FZD10 as a prognostic indicator of liver cancer, a diagnostic marker of metastatic liver cancer, and an intervention target in combination with large-scale clinical samples of liver cancer and prognostic information of patients.

肝癌的复发转移是患者术后治疗面临的重大瓶颈问题，转移导致的死亡高达肿瘤死因的90%。前期工作中我们通过精准选取多发性肝癌样本进行全基因组测序，借助生物信息学分析及功能验证筛选出了肝内转移型肝癌显著高表达基因Frizzled-10 (FZD10)。FZD10为Wnt信号通路的受体，可以调节肿瘤增殖、上皮间质转化及干细胞特性，但FZD10在肝癌肝内转移过程中是否起作用目前未见报道。基于我们前期工作基础，本课题将利用FZD10高、低表达的肝癌细胞系，通过体外细胞实验和体内活体成像的模型，系统研究FZD10对肝癌细胞转移的调控作用；明确FZD10对Wnt／β-catenin信号通路的激活作用及作用靶点，阐明FZD10调控肝癌细胞转移的分子机制；进一步结合大规模肝癌临床样本与病人预后信息，探讨FZD10作为肝癌预后指标、转移型肝癌的诊断标志物及干预靶标的潜在价值。

肝癌的复发转移是患者术后治疗面临的重大瓶颈问题，转移导致的死亡高达肿瘤死因的90%。肝癌干细胞在肝癌的发生发展、复发转移和耐药中起着重要的调控作用，但其具体分子机制并不是十分清楚。本研究中筛选到一个在肝癌干细胞中高表达的基因Frizzled-10 (FZD10)。进一步研究发现FZD10在肝癌干细胞中高表达并与肝癌患者的预后不良相关。功能实验发现过表达FZD10可促进肝癌干细胞的自我更新及肝癌细胞的转移，而干扰FZD10可抑制肝癌干细胞的自我更新及肝癌细胞的转移。RNA-seq及常规生物学研究发现FZD10可上调WNT/β-catenin信号通路和下调Hippo信号通路，即FZD10可促进β-catenin和YAP1的入核。回补实验进一步明确FZD10通过WNT/β-catenin和Hippo信号通路促进肝癌干细胞的自我更新及肝癌细胞的转移。临床研究显示肝癌组织中FZD10高表达与细胞核内β-catenin和YAP1同时高表达的患者预后更差，这些结果提示我们FZD10-β-catenin/YAP1信号轴在肝癌预后判定中的价值。总之，我们的研究结果不仅阐明了肝癌干细胞和肝癌转移调控新的分子机制，而且为肝癌的治疗提供了新的靶点。