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Abstract：
Liver cancer is a prevalent malignant cancer, ranking third in terms of mortality rate. Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer. Hepatocellular carcinoma (HCC) has low expression of focal adhesion kinase (FAK), which increases the risk of metastasis and recurrence. Nevertheless, the efficacy of FAK phosphorylation inhibitors is currently limited. Thus, investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis. This study examined the correlation between FAK expression and the prognosis of HCC. Additionally, we explored the impact of FAK degradation on HCC metastasis through wound healing experiments, transwell invasion experiments, and a xenograft tumor model. The expression of proteins related to epithelial-mesenchymal transition (EMT) was measured to elucidate the underlying mechanisms. The results showed that FAK PROTAC can degrade FAK, inhibit the migration and invasion of HCC cells in vitro, and notably decrease the lung metastasis of HCC in vivo. Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited. Consequently, degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis, holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.
摘要：
肝癌是一种常见的恶性肿瘤,死亡率排名第三。转移和复发是肝癌高死亡率的主要原因。肝细胞癌(HCC)具有低表达的粘着斑激酶(FAK),这增加了转移和复发的风险。然而，目前FAK磷酸化抑制剂的疗效有限.因此，研究FAK影响HCC转移的机制以开发FAK的靶向治疗可能是抑制HCC转移的新策略。本研究探讨了FAK表达与HCC预后的相关性。此外,我们通过伤口愈合实验探讨了FAK降解对HCC转移的影响，Transwell入侵实验,和异种移植肿瘤模型。测量与上皮-间质转化（EMT）相关的蛋白质的表达以阐明潜在的机制。结果表明,FAKPROTAC可以降解FAK,体外抑制肝癌细胞的迁移和侵袭，并显著减少肝癌的体内肺转移。E-cadherin的表达增加和波形蛋白的表达减少表明EMT被抑制。因此,FAK降解通过FAKPROTAC有效抑制肝癌转移，对治疗肝癌和开发创新的抗肿瘤药物具有重要的临床意义。
