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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.

TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin