Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice |
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Authors: | Calvisi Diego F Factor Valentina M Ladu Sara Conner Elizabeth A Thorgeirsson Snorri S |
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Affiliation: | Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute/NIH, Building 37, 37 Convent Drive, Bethesda, MD 20892, USA. |
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Abstract: | 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. |
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Keywords: | AFP, α-fetoprotein dNTP, deoxynucleoside triphosphate HCC, hepatocellular carcinoma LOH, loss of heterozygosity MeIQx, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline MSI, microsatellite instability PCR, polymerase chain reaction RAPD, random amplified polymorphic DNA TGF, transforming growth factor |
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