摘要

具有EGF样结构域1的心脏发育蛋白（HEG1）在胚胎发育和血管生成中起着重要作用，与肿瘤的进展密切相关。然而，HEG1在肝细胞癌（HCC）中的作用尚不清楚。在本研究中，我们探讨了HEG1在肝癌中的临床意义、生物学功能和调控机制，发现HEG1在肝癌细胞系和原发性肿瘤标本中显著上调。此外，HEG1高表达与侵袭性临床病理特征相关。HEG1高表达组的总生存期（OS）和无病生存期（DFS）均短于HEG1低表达组，提示HEG1是预后不良的独立因素。慢病毒介导的HEG1过表达在体外显著促进肝癌细胞迁移、侵袭和上皮-间充质转化（EMT），在体内促进肝内转移、肺转移和EMT。当HEG1沉默时，观察到相反的结果。在机制上，HEG1促进β-catenin的表达并维持其稳定性，导致细胞内β-catenin积累、β-catenin核易位和Wnt信号激活。功能丧失和功能获得实验进一步证实β-catenin在HEG1介导的肝癌侵袭、转移和EMT中起重要作用。总之，HEG1提示预后不良，通过激活Wnt/β-catenin信号通路在HCC侵袭、转移和EMT中发挥重要作用，可作为HCC的一个有潜在价值的预后生物标志物和治疗靶点。

Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.