Separate origins of hepatitis B virus surface antigen-negative foci and hepatocellular carcinomas in transgenic HBsAg (alb/psx) mice.
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.
Crawford
Dana R
DR
Center for Immunology and Microbial Disease, The Albany Medical College, Albany, New York, USA.
Ostrowski
Stephanie
S
Vakharia
Dilip
D
Ilic
Zoran
Z
Sell
Stewart
S
D000418:Albumins / Q000235:genetics; D000818:Animals; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000235:genetics / Q000821:virology*; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000150:complications; D006965:Hyperplasia / Q000821:virology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007834:Lasers; D008099:Liver / Q000473:pathology / Q000821:virology*; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics / Q000821:virology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D042282:Microdissection; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D019076:Transgenes
D000418:Albumins; D006514:Hepatitis B Surface Antigens