Mutations of adenomatous polyposis coli and beta-catenin genes during progression of lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine in rats.

Abstract

In the present study, we investigated mutations of the adenomatous polyposis coli (APC) and beta-catenin genes to clarify possible molecular mechanisms underlying development of lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Male Wistar rats, 6 weeks of age, were given 2000 ppm BHP in drinking water for 12 weeks and then maintained without further treatment until sacrifice at week 25 DNA was extracted from paraffin-embedded tissues, and PCR-single-strand conformation polymorphism analysis, followed by nucleotide sequencing, was performed. No APC mutations were detected in 17 hyperplasias, but 2 of 15 adenomas (13.3%) and 8 of 20 adenocarcinomas (40.0%) showed changes within exon 1 to the mutation cluster region in exon 15. For beta-catenin, no mutations were detected in 17 hyperplasias, but 3 of 15 adenomas (20.0%) and 5 of 20 adenocarcinomas (25.0%) had alterations within or flanking codons corresponding to important phosphorylation sites. Immunohistochemical staining showed beta-catenin protein localized in the cell membranes in the surrounding normal-appearing lung and 216 hyperplasias and localized mainly in the cytoplasm and/or nucleus in 10 of 37 adenomas (27.0%) and 21 of 40 adenocarcinomas (52.5%). These results suggest that the APC-beta-catenin-T-cell factor signaling pathway is involved in the acquisition of growth advantage from adenomas to adenocarcinomas in BHP-induced rat lung carcinogenesis.

• Authors: T Tsujiuchi, M Tsutsumi, Y Sasaki, N Murata, Y Konishi
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 23 Pg. 6611-6 (Dec 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 11118043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carcinogens
• Ctnnb1 protein, rat
• Cytoskeletal Proteins
• Mutagens
• Nitrosamines
• Trans-Activators
• Transcription Factors
• beta Catenin
• diisopropanolnitrosamine

Topics

• Adenocarcinoma (chemically induced, genetics)
• Adenoma (chemically induced, genetics)
• Animals
• Carcinogens (toxicity)
• Cytoskeletal Proteins (genetics)
• DNA Mutational Analysis
• Disease Progression
• Genes, APC (drug effects, genetics)
• Immunohistochemistry
• Lung Neoplasms (chemically induced, genetics, pathology)
• Male
• Mutagens (toxicity)
• Mutation, Missense
• Nitrosamines (toxicity)
• Polymerase Chain Reaction
• Polymorphism, Single-Stranded Conformational
• Rats
• Rats, Wistar
• Signal Transduction (physiology)
• Trans-Activators
• Transcription Factors (physiology)
• beta Catenin