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(American Journal of Pathology. 2006;169:223-232.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051284

Separate Origins of Hepatitis B Virus Surface Antigen-Negative Foci and Hepatocellular Carcinomas in Transgenic HBsAg (alb/psx) Mice

Dana R. Crawford*, Stephanie Ostrowski{dagger}, Dilip Vakharia{dagger}, Zoran Ilic{ddagger} and Stewart Sell{dagger}{ddagger}

From the Center for Immunology and Microbial Disease,* The Albany Medical College; the Wadsworth Center,{dagger} New York State Department of Health; and the Ordway Research Institute,{ddagger} Albany, New York

We have examined the development and transgene expression in liver lesions of transgenic mice bearing the hepatitis B surface antigen (HBsAg) gene of hepatitis B virus under the control of the albumin promoter (alb/psx) to study liver regeneration and hepatocellular carcinoma (HCC) associated with hepatitis B virus infection. Storage of the HBsAg in the endoplasmic reticulum precedes loss of liver cells and regenerative hyperplastic nodules that do not express HBsAg. Histological analysis indicated that HBsAg-negative foci and nodules arose from liver progenitor cells in the portal zone and lacked mRNA expression. Genomic DNA from eight of nine HBsAg-negative laser capture-excised liver foci showed loss of part of the alb/psx gene, whereas no loss of the actin gene was observed. The alb/psx DNA was intact in adjacent HBsAg-positive tissue. Sequencing of polymerase chain reaction products suggested that alterations in the HBsAg transgene in HBsAg-negative foci occurred via large-scale deletions as opposed to single-site mutations. Southern blot analysis of HCC from 2-year-old transgenic HBsAg mice, however, revealed an intact alb/psx gene. Thus, HBsAg-negative progenitor cells with deletions in the transgene appear to be responsible for compensatory regeneration of the liver, whereas HCCs arise from clonal expansion of hepatocytes with intact alb/psx transgenes.






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Copyright © 2006 by the American Society for Investigative Pathology.