Calvisi, Diego Francesco and Factor, Valentina M. and Ladu, Sara and Conner, Elizabeth A. and Thorgeirsson, Snorri S. (2004) Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice. Gastroenterology, Vol. 126 (5), p. 1374-1386. ISSN 0016-5085. Article.
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Background & Aims: Human liver cancer can be divided into 2 categories that are characterized by activation of β-catenin and genomic instability. Here we investigate whether similar categories exist among 5 transgenic models of liver cancer, including c-myc, transforming growth factor-α, E2F-1, c-myc/transforming growth factor-α, 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. β-Catenin mutations and deletions were analyzed by polymerase chain reaction and sequencing screening. Cellular localization of β-catenin and expression of α-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-α mouse) and activation of β-catenin (exemplified by the c-myc/E2F-1 mouse). The c-myc/transforming growth factor-α 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 β-catenin activation. The genomic instability was evident from the early dysplastic stage and occurred concomitantly with increased expression of α-fetoprotein. The c-myc/E2F-1 tumors were characterized by a high frequency of β-catenin activation in the presence of a relatively stable genome and low α-fetoprotein levels. Conclusions: We have identified 2 prototype experimental models, i.e., c-myc/transforming growth factor-α and c-myc/E2F-1 mice, for the 2 categories of human hepatocellular carcinoma characterized by genomic instability and β-catenin activation, respectively. These mouse models will assist in the elucidation of the molecular basis of human hepatocellular carcinoma.
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