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 Ogawa, K. Articles by Tokusashi, Y. Search for Related Content PubMed PubMed Citation Articles by Ogawa, K. Articles by Tokusashi, Y.

ß-Catenin Mutations Are Frequent in Hepatocellular Carcinomas but Absent in Adenomas Induced by Diethylnitrosamine in B6C3F1 Mice¹

Department of Pathology, Asahikawa Medical College, Asahikawa 078-8510, Japan

Activating mutations in the region of the ß-catenin gene corresponding to the NH₂-terminal phosphorylation sites of glycogen synthetase kinase 3ß have been causally implicated in carcinogenesis. In this study, the ß-catenin exon 3 was examined in hepatic lesions induced by diethylnitrosamine in B6C3F1 mice. PCR and DNA sequencing detected seven ß-catenin mutations in 13 samples dissected from hepatocellular carcinoma tissues, but none in 14 hepatic adenomas. All of the mutations were found in codon 41 encoding a threonine residue, one of the possible glycogen synthetase kinase-3ß phosphorylation sites. Although ß-catenin protein was immunohistochemically stained mainly on the cell membrane in preneoplastic hepatocytic foci and most adenomas, as observed in normal hepatocytes, it was detected in the cytoplasm and nuclei in addition to the cell membrane, indicating stabilization of the protein in HCCs. This shift in staining was observed not only in tumors with mutations, but also in examples lacking exon 3 mutations. Our data demonstrate that ß-catenin alterations may be important for malignant progression during multistep hepatic carcinogenesis in mice.

This article has been cited by other articles:

				Omega-3 polyunsaturated fatty acids inhibit hepatocellular carcinoma cell growth through blocking {beta}-catenin and cyclooxygenase-2 Mol. Cancer Ther., November 1, 2009; 8(11): 3046 - 3055.

				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. A. Jackson, I. Lea, A. Rashid, S. D. Peddada, and J. K. Dunnick Genetic Alterations in Cancer Knowledge System: Analysis of Gene Mutations in Mouse and Human Liver and Lung Tumors Toxicol. Sci., April 1, 2006; 90(2): 400 - 418. [Abstract] [Full Text] [PDF]

				M. P.A. Ebert, J. Yu, J. Hoffmann, A. Rocco, C. Rocken, S. Kahmann, O. Muller, M. Korc, J. J. Sung, and P. Malfertheiner Loss of Beta-Catenin Expression in Metastatic Gastric Cancer J. Clin. Oncol., May 1, 2003; 21(9): 1708 - 1714. [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]

				N. Harada, H. Miyoshi, N. Murai, H. Oshima, Y. Tamai, M. Oshima, and M. M. Taketo Lack of Tumorigenesis in the Mouse Liver after Adenovirus-mediated Expression of a Dominant Stable Mutant of {beta}-Catenin Cancer Res., April 1, 2002; 62(7): 1971 - 1977. [Abstract] [Full Text] [PDF]

				M. P.A. Ebert, G. Fei, S. Kahmann, O. Muller, J. Yu, J. J.Y. Sung, and P. Malfertheiner Increased {beta}-catenin mRNA levels and mutational alterations of the APC and {beta}-catenin gene are present in intestinal-type gastric cancer Carcinogenesis, January 1, 2002; 23(1): 87 - 91. [Abstract] [Full Text] [PDF]

				S. P. Anderson, C. S. Dunn, R. C. Cattley, and J.C. Corton Hepatocellular proliferation in response to a peroxisome proliferator does not require TNF{alpha} signaling Carcinogenesis, November 1, 2001; 22(11): 1843 - 1851. [Abstract] [Full Text] [PDF]

				D. F. Calvisi, V. M. Factor, R. Loi, and S. S. Thorgeirsson Activation of {beta}-Catenin during Hepatocarcinogenesis in Transgenic Mouse Models: Relationship to Phenotype and Tumor Grade Cancer Res., March 1, 2001; 61(5): 2085 - 2091. [Abstract] [Full Text]

				H.-C. Hsu, Y.-M. Jeng, T.-L. Mao, J.-S. Chu, P.-L. Lai, and S.-Y. Peng {beta}-Catenin Mutations Are Associated with a Subset of Low-Stage Hepatocellular Carcinoma Negative for Hepatitis B Virus and with Favorable Prognosis Am. J. Pathol., September 1, 2000; 157(3): 763 - 770. [Abstract] [Full Text] [PDF]

				C. H. Anna, R. C. Sills, J. F. Foley, P. S. Stockton, T.-V. Ton, and T. R. Devereux {beta}-Catenin Mutations and Protein Accumulation in All Hepatoblastomas Examined from B6C3F1 Mice Treated with Anthraquinone or Oxazepam Cancer Res., June 1, 2000; 60(11): 2864 - 2868. [Abstract] [Full Text] [PDF]