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 1 , Chun-Jen Liu 1, 2, 3 , Tung-Hung Su 1, 2, 3 , Huei-Ru Cheng 1 , Yung-Ming Jeng 4, 5 , Hsiu-Lin Lin 3 , Chih-Chiang Wang 1 , Jia-Horng Kao 1, 2, 3 , Pei-Jer Chen 1, 2, 3 , Ding-Shinn Chen 1, 2, 3 , Hui-Lin Wu 1, 3 1 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 3 Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan 4 Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan Correspondence to: Hui-Lin Wu, email: huilinwu@ntu.edu.tw Chun-Jen Liu, email: cjliu@ntu.edu.tw 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 ABSTRACT 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.