去泛素化酶USP11与多种肿瘤的发生发展密切相关。然而，其在肝癌中的表达及生物学功能依然不清。前期预实验发现：USP11在肝癌组织和细胞中异常高表达并与患者不良预后相关。USP11通过NAKED1促进肝癌细胞侵袭转移能力。RNA-seq结合质谱分析发现，USP11通过与EZH2结合，减少其泛素化从而稳定其表达，进而抑制NAKED1的表达。基于以上结果提出假说：USP11/EZH2/NAKED1轴介导肝癌细胞的侵袭转移能力。为验证此假说，本项目拟通过设计突变体和免疫共沉淀等明确USP11与EZH2的结合区域及泛素化调控机制；通过荧光素酶报告基因和功能恢复实验明确USP11通过EZH2负向调控NAKED1的转录，从而解除其对下游经典Wnt信号通路的抑制，最终促进肝癌细胞侵袭转移；最后通过动物模型和临床样本进行验证。本项目首次阐述该调控轴在肝癌侵袭转移中的作用机制，为肝癌诊断和治疗提供理论依据。

Deubiquitinating enzymes USP11 is closely related to the development and progression of many tumors. However, the expression pattern and biological function of USP11 in hepatocellular carcinoma (HCC) still needs to be further addressed. Our previous study has found out that USP11 was abnormal higher expression in HCC tissues and cells, and associated with patients’ poor prognosis. USP11 promoted HCC cell invasion and migration potency via NAKED1. RNA-seq and mass spectrometry analysis showed that USP11 interacted with and stabilized EZH2 by promoting its deubiquitination, which further inhibited the expression of NAKED1. Based on the above results, we suppose that USP11/EZH2/NAKED1 axis promotes HCC cell invasion and migration ability. In order to verify this hypothesis, we will uncover the combination region and regulation mechanism of ubiquitination between USP11 and EZH2 via designing of mutants and co-Ip. What’s more, through the luciferase report gene and functional recovery experiment, we plan to investigate the mechanism of USP11 negatively regulating NAKED1 transcription via EZH2, which further remove the inhibition of classic Wnt signaling pathways and ultimately promote the invasion and metastasis of HCC cells. Finally, we suppose to confirm our results through the nude mouse tumorigenicity assay and clinical samples in vitro. In this study, we study the mechanism of this axis on regulating HCC cell invasion and migration ability for the first time. The goal of this study is expected to provide a theoretical basis for clinical diagnosis and treatment of HCC.