Research Papers:

Characterization of metastatic tumor antigen 1 and its interaction with hepatitis B virus X protein in NF-κB signaling and tumor progression in a woodchuck hepatocellular carcinoma model

Yung-Tsung Li, Chun-Jen Liu, Tung-Hung Su, Huei-Ru Cheng, Yung-Ming Jeng, Hsiu-Lin Lin, Chih-Chiang Wang, Jia-Horng Kao, Pei-Jer Chen, Ding-Shinn Chen and Hui-Lin Wu _

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Oncotarget. 2016; 7:47173-47185. https://doi.org/10.18632/oncotarget.9986

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Yung-Tsung Li1, Chun-Jen Liu1,2,3, Tung-Hung Su1,2,3, Huei-Ru Cheng1, Yung-Ming Jeng4,5, Hsiu-Lin Lin3, Chih-Chiang Wang1, Jia-Horng Kao1,2,3, Pei-Jer Chen1,2,3, Ding-Shinn Chen1,2,3, Hui-Lin Wu1,3

1Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

3Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan

4Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan

5Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

Correspondence to:

Hui-Lin Wu, email: [email protected]

Chun-Jen Liu, email: [email protected]

Keywords: metastatic tumor antigen 1 (MTA1), hepatitis B virus (HBV), hepatocellular carcinoma (HCC), woodchuck, splicing variant

Received: February 03, 2016     Accepted: May 28, 2016     Published: June 13, 2016


The metastatic tumor antigen 1 (MTA1) protein is associated with tumor invasiveness and poor prognosis in patients with hepatocellular carcinoma (HCC), particularly in those with hepatitis B virus (HBV)-related HCC. Chronically woodchuck hepatitis virus (WHV)-infected woodchuck is an ideal animal model for studying the pathogenesis of HBV-associated liver diseases, including HCC. To investigate the roles of MTA1 in HBV-associated hepatocarcinogenesis in the woodchuck model, we cloned the woodchuck MTA1 (wk-MTA1) complementary (c)DNA and characterized its molecular functions. The sequence and organization of the wk-MTA1 protein were highly conserved among different species. Similar to its expression in human HCC, wk-MTA1 was upregulated in woodchuck HCC, as determined at RNA and protein levels. Furthermore, an MTA1-spliced variant, wk-MTA1dE4, was overexpressed in woodchuck HCC, and it was attributed to approximately 50% of the total transcripts. The percentage of wk-MTA1dE4-overexpressed woodchuck HCCs was higher than that of the total wk-MTA1-overexpressed HCCs (77.8% vs 61.1%) and wk-MTA1dE4 may represent a more sensitive marker than the total wk-MTA1 in woodchuck HCC. We overexpressed or knocked down wk-MTA1 in a woodchuck HCC cell line and demonstrated that wk-MTA1 could interact with the WHV X protein (WHx) and play indispensable roles in WHx-mediated NF-κB activation and tumor cell migration- and invasion-promoting activities. In conclusion, our results support the hypothesis that woodchuck HCC recapitulates HBV-associated HCC with respect to the molecular characteristics of MTA1 and provides new clues for conducting mechanistic studies of MTA1 in HBV-associated hepatocarcinogenesis, including the possible clinical significance of wk-MTA1dE4.

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