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.
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.
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yung-Tsung
YT
Li
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Chun-Jen
CJ
Liu
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Tung-Hung
TH
Su
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Huei-Ru
HR
Cheng
Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
Yung-Ming
YM
Jeng
Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Hsiu-Lin
HL
Lin
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chih-Chiang
CC
Wang
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Jia-Horng
JH
Kao
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Pei-Jer
PJ
Chen
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Ding-Shinn
DS
Chen
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.|Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
Hui-Lin
HL
Wu
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008392:Marmota; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
D000951:Antigens, Neoplasm; D016328:NF-kappa B; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein
hepatitis B virus (HBV); hepatocellular carcinoma (HCC); metastatic tumor antigen 1 (MTA1); splicing variant; woodchuck