Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice

Gastroenterology. 2004 May;126(5):1374-86. doi: 10.1053/j.gastro.2004.02.014.


Background & aims: Human liver cancer can be divided into 2 categories that are characterized by activation of beta-catenin and genomic instability. Here we investigate whether similar categories exist among 5 transgenic models of liver cancer, including c-myc, transforming growth factor-alpha, E2F-1, c-myc/transforming growth factor-alpha, and c-myc/E2F-1 mice.

Methods: The random amplified polymorphic DNA method was used to assess the overall genomic instability, and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. beta-Catenin mutations and deletions were analyzed by polymerase chain reaction and sequencing screening. Cellular localization of beta-catenin and expression of alpha-fetoprotein, a prognostic marker of hepatocellular carcinoma, were investigated by immunohistochemistry.

Results: Liver tumors from the transgenic mice could be divided into 2 broad categories characterized by extensive genomic instability (exemplified by the c-myc/transforming growth factor-alpha mouse) and activation of beta-catenin (exemplified by the c-myc/E2F-1 mouse). The c-myc/transforming growth factor-alpha tumors displayed extensive genomic instability with recurrent loss of heterozygosity at chromosomes 1, 2, 4, 6, 7, 9, 12, 14, and X and a low rate of beta-catenin activation. The genomic instability was evident from the early dysplastic stage and occurred concomitantly with increased expression of alpha-fetoprotein. The c-myc/E2F-1 tumors were characterized by a high frequency of beta-catenin activation in the presence of a relatively stable genome and low alpha-fetoprotein levels.

Conclusions: We have identified 2 prototype experimental models, i.e., c-myc/transforming growth factor-alpha and c-myc/E2F-1 mice, for the 2 categories of human hepatocellular carcinoma characterized by genomic instability and beta-catenin activation, respectively. These mouse models will assist in the elucidation of the molecular basis of human hepatocellular carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Proteins*
  • Cytoskeletal Proteins / genetics*
  • Cytoskeletal Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • Gene Deletion*
  • Gene Frequency
  • Genes, myc
  • Genomic Instability*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Loss of Heterozygosity
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Phenotype
  • Quinoxalines / pharmacology
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transforming Growth Factor alpha / genetics
  • alpha-Fetoproteins / metabolism
  • beta Catenin


  • CTNNB1 protein, mouse
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2f1 protein, mouse
  • Quinoxalines
  • Trans-Activators
  • Transcription Factors
  • Transforming Growth Factor alpha
  • alpha-Fetoproteins
  • beta Catenin
  • 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline