Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma.
Hepatitis B virus (HBV)-encoded X antigen (HBxAg) contributes to the development of hepatocellular carcinoma (HCC). A frequent characteristic of HCC is reduced or absent expression of the cell adhesion protein, E-cadherin, although it is not known whether HBxAg plays a role. To address this, the levels of E-cadherin were determined in HBxAg-positive and -negative HepG2 cells in culture, and in tumor and surrounding nontumor liver from a panel of HBV carriers. The results showed an inverse relationship between HBxAg and E-cadherin expression both in tissue culture and in vivo. In HBxAg-positive cells, E-cadherin was suppressed at both the mRNA and protein levels. This was associated with hypermethylation of the E-cadherin promoter. Depressed E-cadherin correlated with HBxAg trans-activation function, as did the migration of HepG2 cells in vitro. Decreased expression of E-cadherin was also associated with the accumulation of beta-catenin in the cytoplasm and/or nuclei in tissues and cell lines, which is characteristic of activated beta-catenin. Additional work showed that HBxAg-activated beta-catenin. Together, these results suggest that the HBxAg is associated with decreased expression of E-cadherin, accumulation of beta-catenin in the cytoplasm and nucleus, and increased cell migration, which may contribute importantly to hepatocarcinogenesis.
Liu
J
J
Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA, and State Key Laboratory for Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Xi'an, Shaanxi, Peoples Republic of China.
Lian
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Han
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Waye
M M Y
MM
Wang
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H
Wu
M-C
MC
Wu
K
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Ding
J
J
Arbuthnot
P
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Kew
M
M
Fan
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D
Feitelson
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MA
D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D002465:Cell Movement; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D019175:DNA Methylation; D015536:Down-Regulation; D006515:Hepatitis B virus; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism
D015820:Cadherins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; D051176:beta Catenin; C057628:hepatitis B virus X protein