This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Calvisi, D. F. Articles by Thorgeirsson, S. S. Search for Related Content PubMed PubMed Citation Articles by Calvisi, D. F. Articles by Thorgeirsson, S. S.

Activation of ß-Catenin during Hepatocarcinogenesis in Transgenic Mouse Models

Relationship to Phenotype and Tumor Grade

Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255

Mutations affecting phosphorylation sites in the ß-catenin gene have been implicated in the development of human and rodent hepatocellular carcinomas (HCCs). To further investigate the involvement of this gene in hepatocarcinogenesis, we used several transgenic mouse models of hepatic tumors induced by overexpression of c-myc in the liver either alone or in combination with transforming growth factor (TGF) or TGF-ß1. Activation of ß-catenin, as judged by the presence of mutations and/or nuclear translocation of the protein, was most frequent in liver tumors from c-myc (4/17; 23.5%) and c-myc/TGF-ß1 (6/18; 33.3%) transgenic mice. However, it was very rare in faster growing and histologically more aggressive HCCs developed in c-myc/TGF- mice (1/20; 5%). Administration of diethylnitrosamine, phenobarbital, or 2-amino-3,8-diethylimidazo[4,5-f]quinoxaline did not significantly affect the occurrence of ß-catenin mutations. Notably, nuclear accumulation of ß-catenin was observed only in adenomas and highly differentiated carcinomas with eosinophilic phenotype. Furthermore, preneoplastic lesions with eosinophilic phenotype frequently displayed focal nuclear positivity, colocalized with areas of high proliferation. In contrast, basophilic and clear-cell foci, as well as pseudo-glandular and poorly differentiated HCCs, exhibited a normal or reduced membranous immunoreactivity for ß-catenin. These studies suggest that nuclear translocation of ß-catenin and activation of Wingless/Wnt signaling may represent an early event in liver carcinogenesis, providing a growth advantage in a subset of hepatic tumors with a more differentiated phenotype.

This article has been cited by other articles:

				B.-R. Wei, J. B. Edwards, S. B. Hoover, H. S. Tillman, L. T. Reed, R. C. Sills, and R. M. Simpson Altered {beta}-Catenin Accumulation in Hepatocellular Carcinomas of Diethylnitrosamine-Exposed Rhesus Macaques Toxicol Pathol, December 1, 2008; 36(7): 972 - 980. [Abstract] [Full Text] [PDF]

				M. R. De Miglio, P. Virdis, D. F. Calvisi, D. Mele, M. R. Muroni, M. Frau, F. Pinna, M. L. Tomasi, M. M. Simile, R. M. Pascale, et al. Identification and chromosome mapping of loci predisposing to colorectal cancer that control Wnt/{beta}-catenin pathway and progression of early lesions in the rat Carcinogenesis, November 1, 2007; 28(11): 2367 - 2374. [Abstract] [Full Text] [PDF]

				C.-A. Renard, C. Labalette, C. Armengol, D. Cougot, Y. Wei, S. Cairo, P. Pineau, C. Neuveut, A. de Reynies, A. Dejean, et al. Tbx3 Is a Downstream Target of the Wnt/{beta}-Catenin Pathway and a Critical Mediator of {beta}-Catenin Survival Functions in Liver Cancer Cancer Res., February 1, 2007; 67(3): 901 - 910. [Abstract] [Full Text] [PDF]

				A. N.M. Fischer, B. Herrera, M. Mikula, V. Proell, E. Fuchs, J. Gotzmann, R. Schulte-Hermann, H. Beug, and W. Mikulits Integration of Ras subeffector signaling in TGF-{beta} mediated late stage hepatocarcinogenesis Carcinogenesis, May 1, 2005; 26(5): 931 - 942. [Abstract] [Full Text] [PDF]

				D. F. Calvisi and S. S. Thorgeirsson Molecular Mechanisms of Hepatocarcinogenesis in Transgenic Mouse Models of Liver Cancer Toxicol Pathol, January 1, 2005; 33(1): 181 - 184. [Abstract] [Full Text] [PDF]

				S. Loeppen, C. Koehle, A. Buchmann, and M. Schwarz A {beta}-catenin-dependent pathway regulates expression of cytochrome P450 isoforms in mouse liver tumors Carcinogenesis, January 1, 2005; 26(1): 239 - 248. [Abstract] [Full Text] [PDF]

				Y. Yamamoto, R. Moore, T. L. Goldsworthy, M. Negishi, and R. R. Maronpot The Orphan Nuclear Receptor Constitutive Active/Androstane Receptor Is Essential for Liver Tumor Promotion by Phenobarbital in Mice Cancer Res., October 15, 2004; 64(20): 7197 - 7200. [Abstract] [Full Text] [PDF]

				D. F. Calvisi, S. Ladu, V. M. Factor, and S. S. Thorgeirsson Activation of {beta}-catenin provides proliferative and invasive advantages in c-myc/TGF-{alpha} hepatocarcinogenesis promoted by phenobarbital Carcinogenesis, June 1, 2004; 25(6): 901 - 908. [Abstract] [Full Text] [PDF]

				J. Gotoh, M. Obata, M. Yoshie, S. Kasai, and K. Ogawa Cyclin D1 over-expression correlates with {beta}-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3{beta} and ERK1/2 in mouse hepatic carcinogenesis Carcinogenesis, March 1, 2003; 24(3): 435 - 442. [Abstract] [Full Text] [PDF]

				K. Nicholes, S. Guillet, E. Tomlinson, K. Hillan, B. Wright, G. D. Frantz, T. A. Pham, L. Dillard-Telm, S. P. Tsai, J.-P. Stephan, et al. A Mouse Model of Hepatocellular Carcinoma : Ectopic Expression of Fibroblast Growth Factor 19 in Skeletal Muscle of Transgenic Mice Am. J. Pathol., June 1, 2002; 160(6): 2295 - 2307. [Abstract] [Full Text] [PDF]