Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Surgery, University of Virginia, Charlottesville, VA, USA.
Carcinogenesis. 2020 Jul 10;41(5):571-581. doi: 10.1093/carcin/bgz133.
Cripto-1 (CR1), an oncofetal protein, had been implied to reactivate in some cancers. However, the relationship between CR1 expression and patient outcomes and the tumor biological function of CR1 contributing to invasion and metastasis in hepatocellular carcinoma (HCC) is poorly defined. In this study, we demonstrated that CR1 was expressed in over 80% of HCCs in a training cohort (n = 242) and a validation cohort (n = 159). High CR1 expression was significantly correlated with aggressive HCC phenotypes (i.e. portal vein tumor thrombus, microscopic vascular invasion, multiple tumors and poor tumor differentiation). In both the training and validation cohorts, patients with high CR1 expression had remarkably shorter disease-free survival and overall survival rates than those with low CR1 expression. A series in vitro and in vivo assays showed that CR1 substantially promoted HCC cell migration, invasion and metastasis. Mechanistically, we demonstrated that CR1 induced HCC cells to undergo epithelial-mesenchymal transition through activating the Akt/NFκB/p65 signaling. Chromatin immunoprecipitation assay showed that NFκB/p65 enhanced CR1 expression by binding its promoter. Thus, CR1 and NFκB/p65 form a positive feedback loop that sustained the process of migration and invasion of HCC. Therefore, CR1 plays an important role in HCC invasion and metastasis and may be an effective and reliable prognostic biomarker for HCC recurrence after resection. Targeting CR1 may be a promising treatment for HCC.
CR1（Crypto-1）是一种癌胚蛋白，已被证实与某些癌症的激活有关。然而，CR1 表达与患者预后之间的关系以及 CR1 促进肝癌（HCC）侵袭和转移的肿瘤生物学功能尚不清楚。在本研究中，我们在一个训练队列（n=242）和一个验证队列（n=159）中证实 CR1 在超过 80%的 HCC 中表达。高 CR1 表达与侵袭性 HCC 表型（即门静脉肿瘤血栓、微血管侵犯、多发肿瘤和低肿瘤分化）显著相关。在训练队列和验证队列中，CR1 高表达的患者无病生存率和总生存率均明显低于 CR1 低表达的患者。一系列体外和体内实验表明，CR1 可显著促进 HCC 细胞迁移、侵袭和转移。在机制上，我们证明 CR1 通过激活 Akt/NFκB/p65 信号通路诱导 HCC 细胞发生上皮间质转化。染色质免疫沉淀实验表明，NFκB/p65 通过结合其启动子增强了 CR1 的表达。因此，CR1 和 NFκB/p65 形成一个正反馈回路，维持 HCC 迁移和侵袭的过程。因此，CR1 在 HCC 的侵袭和转移中起重要作用，可能是 HCC 切除后复发的有效和可靠的预后标志物。靶向 CR1 可能是 HCC 的一种有前途的治疗方法。
