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

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 ?-catenin, a positive transcriptional regulator of ZEB1. Accordingly, we found that TXNDC12 interacted with ?-catenin and that the thioredoxin-like domain of TXNDC12 was essential for the interaction between TXNDC12 and ?-catenin as well as for TXNDC12-mediated ?-catenin activation. Moreover, high levels of TXNDC12 in clinical HCC tissues correlated with elevated nuclear ?-catenin levels and predicted worse overall and disease-free survival. In summary, our study demonstrated that TXNDC12 could activate ?-catenin via protein-protein interaction and promote ZEB1-mediated EMT and HCC metastasis.

SUBMITTER: Yuan K

PROVIDER: S-EPMC7206186 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Yuan Kefei K Xie Kunlin K Lan Tian T Xu Lin L Chen Xiangzheng X Li Xuefeng X Liao Mingheng M Li Jiaxin J Huang Jiwei J Zeng Yong Y Wu Hong H

Cell death and differentiation 20190930 4

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 investig ...[more]

PMID: 31570854

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Project description:Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.

Dataset Information

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

Publications

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

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