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

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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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 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.

Item Type:Article
ID Code:1255
Uncontrolled Keywords:α-fetoprotein, deoxynucleoside triphosphate, hepatocellular carcinoma, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, microsatellite instability, polymerase chain reaction, random amplified polymorphic DNA, transforming growth factor (TGA)
Subjects:Area 06 - Scienze mediche > MED/04 Patologia generale
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Copyright Holders:© 2004 American Gastroenterological Association
Deposited On:18 Aug 2009 10:04

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