TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin
TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin
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TXNDC12通过激活β-catenin促进肝细胞癌细胞的EMT和转移
DOI：
10.1038/s41418-019-0421-7
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发表时间：
2020-04-01
影响因子：
12.4
通讯作者：
Wu, Hong
中科院分区：
文献类型：
--
作者：
Yuan, Kefei;Xie, Kunlin;Wu, Hong
转移是导致肝细胞癌预后不良的主要因素之一。然而，肝细胞癌转移的潜在机制在很大程度上仍不清楚。在这里，我们发现TXNDC12，一种硫氧还蛋白样蛋白，在高转移的肝癌细胞系以及肝细胞癌患者的门静脉癌栓和肺转移组织中上调。我们发现TXNDC12的增强表达促进了体内和体外的转移。随后的机制研究表明，TXNDC12通过上调ZEB1介导的上皮-间充质转化(EMT)过程促进肿瘤转移。我们随后发现，TXNDC12的过表达刺激了ZEB1的正转录调节因子β-连环蛋白的核转位和激活。因此，我们发现TXNDC12与β-连环蛋白相互作用，并且TXNDC12的硫氧还蛋白样结构域对于TXNDC12与β-连环蛋白的相互作用以及TXNDC12介导的β-连环蛋白的激活是必不可少的。此外，临床肝细胞癌组织中高水平的TXNDC12与核β-连环蛋白水平升高相关，并预示着较差的总体和无病生存率。综上所述，我们的研究表明，TXNDC12可以通过蛋白-蛋白相互作用激活β-连环蛋白，促进ZEB1介导的内膜转移和肝细胞癌的转移。
Metastasis is one of the main contributors to the poor prognosis of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC metastasis remains largely unknown. Here, we showed that TXNDC12, a thioredoxin-like protein, was upregulated in highly metastatic HCC cell lines as well as in portal vein tumor thrombus and lung metastasis tissues of HCC patients. We found that the enforced expression of TXNDC12 promoted metastasis both in vitro and in vivo. Subsequent mechanistic investigations revealed that TXNDC12 promoted metastasis through upregulation of the ZEB1-mediated epithelial–mesenchymal transition (EMT) process. We subsequently showed that TXNDC12 overexpression stimulated the nuclear translocation and activation of β-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with β-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and β-catenin as well as for TXNDC12-mediated β-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear β-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate β-catenin via protein–protein interaction and promote ZEB1-mediated EMT and HCC metastasis.