Carcinogenesis, Vol. 24, No. 1, 91-97,
January 2003
© 2003 Oxford University Press
CARCINOGENESIS |
ß-Catenin mutation is selected during malignant transformation in colon carcinogenesis
1 Department of Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705 and
2 Department of Pathology, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan
Activating mutations in the ß-catenin gene is thought to be responsible for the excessive ß-catenin signaling involved in the majority of colon carcinomas in rodent models. Our recent study which indicated that ß-catenin mutations are present frequently in early dysplastic lesions of rat colon induced by a colon-specific carcinogen, azoxymethane led us to perform more specifically a comparative study regarding types of the ß-catenin mutation as well as K-ras mutations between such early appearing lesions and colon tumors. Male F344 rats, 6 weeks old, received s.c. injections of azoxymethane (15 mg/kg body weight) once a week for 3 weeks, and were killed at 16 and 46 weeks of age. Colons of animals killed at 16 weeks of age were processed for early altered lesions. Colon tumors from animals killed at 46 weeks of age were evaluated histopathologically. Laser capture microdissection system was used to obtain DNA of epithelial cells in both intramucosal lesions and colon tumors. After amplification of exon 3 of the ß-catenin gene and exon 1 of the K-ras gene, the products were then sequenced directly in both directions. Mutations in the exon 3 of ß-catenin gene were detected in 22 of 56 early lesions (39.3%) and 21 of 37 colon cancers (56.8%). Remarkably, all ß-catenin mutations detected in the colon tumors converged at codons encoding functionally important residues that may directly mediate ß-catenin degradation, whereas mutations in the early appearing lesions were found to be scattered in the exon 3 of the gene. K-ras mutations were also detected in 24 of 56 early lesions (42.9%) and 11 of 37 colon cancers (29.7%). All K-ras mutations converged at codon 12 and codon 13, even in the early lesions. The results of this study provide evidence for the first time that ß-catenin mutation is selected during the colon carcinogenesis. Our results also suggest that the activation of ß-catenin signaling pathway is not only an initiating event, but also plays a pivotal role in the promotion stage of colorectal carcinogenesis.
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