Abstract
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.
Highlights
Liver cancer, of which 70–90% are hepatocellular carcinoma (HCC), is the second leading cause of cancer deathThese authors contributed : Kefei Yuan, Kunlin Xie, Tian LanEdited by P
Upregulated expression of Thioredoxin domain-containing protein 12 (TXNDC12) in HCC was confirmed by gene expression analysis based on a dataset from The Cancer Genome Atlas (TCGA) and three Gene Expression Omnibus (GEO) datasets (Fig. 1d)
The results showed that the expression levels of TXNDC12 were lowest in normal hepatocytes (THLE-2) and were significantly higher in the highly metastatic cell lines (SNU449 and HCCLM3) than in weakly metastatic cell lines (Hep3B, Huh7, and PLC/PRF/5) (Fig. 1e)
Summary
Of which 70–90% are hepatocellular carcinoma (HCC), is the second leading cause of cancer death. Recent studies have raised concerns about the actual contribution of EMT to metastasis in lung cancer [6] and pancreatic cancer [7], the experimental results acquired in HCC still support the idea that EMT plays a pivotal role in HCC metastasis. Loss of E-cadherin, a typical marker of epithelial cells, is one of the key features of the EMT process and has been implicated in tumor metastasis [12]. A portion of the β-catenin detaches from the complex and translocates into the nucleus to perform its transcriptional regulatory function. Enforced expression of TXNDC12 stimulated the metastatic potential of HCC cells via induction of the EMT process. Our data indicate that the overexpression of TXNDC12 promotes HCC metastasis through β-cateninmediated induction of EMT and that TXNDC12 has the potential to be a prognostic factor and therapeutic target of HCC
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