Mutations of adenomatous polyposis coli and beta-catenin genes during progression of lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine in rats.
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.
Tsujiuchi
T
T
Department of Oncological Pathology, Cancer Center, Nara Medical University, Kashihara, Japan.
Tsutsumi
M
M
Sasaki
Y
Y
Murata
N
N
Konishi
Y
Y
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D017491:Genes, APC / Q000187:drug effects / Q000235:genetics*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D009153:Mutagens / Q000633:toxicity; D020125:Mutation, Missense; D009602:Nitrosamines / Q000633:toxicity; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology; D051176:beta Catenin
D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D009153:Mutagens; D009602:Nitrosamines; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C012457:diisopropanolnitrosamine