Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice.
OBJECTIVE
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.
Calvisi
Diego F
DF
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute/NIH, Building 37, 37 Convent Drive, Bethesda, MD 20892, USA.
Factor
Valentina M
VM
Ladu
Sara
S
Conner
Elizabeth A
EA
Thorgeirsson
Snorri S
SS
D000818:Animals; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D017353:Gene Deletion; D005787:Gene Frequency; D016259:Genes, myc; D042822:Genomic Instability; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D011810:Quinoxalines / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics; D000509:alpha-Fetoproteins / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011810:Quinoxalines; D015534:Trans-Activators; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D000509:alpha-Fetoproteins; D051176:beta Catenin; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline