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.

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.

• Authors: 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, Hui-Lin Wu
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 30 Pg. 47173-47185 (Jul 26 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27323415 (Publication Type: Journal Article)

Chemical References

• Antigens, Neoplasm
• NF-kappa B
• Trans-Activators
• Viral Regulatory and Accessory Proteins
• hepatitis B virus X protein

Topics

• Amino Acid Sequence
• Animals
• Antigens, Neoplasm (metabolism)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Marmota
• NF-kappa B (metabolism)
• Signal Transduction
• Trans-Activators (metabolism)
• Transfection
• Viral Regulatory and Accessory Proteins