TY - JOUR
T1 - β-Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas
AU - Tsukamoto, Tetsuya
AU - Yamamoto, Masami
AU - Ogasawara, Naotaka
AU - Ushijima, Toshikazu
AU - Nomoto, Tomoko
AU - Fujita, Hirofumi
AU - Matsushima, Taijiro
AU - Nozaki, Koji
AU - Cao, Xueyuan
AU - Tatematsu, Masae
PY - 2003/12
Y1 - 2003/12
N2 - Aberrant Wnt/β-catenin signaling caused by mutations in exon 3 of the β-catenin gene has been identified in a number of human malignancies, including stomach cancer. However, studies of mutation frequency have yielded conflicting results, and timing during progression remains largely unknown. In this study, we utilized an animal model to address this question. A total of 20 ACI male rats were treated with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) in the drinking water and 22 induced differentiated adenocarcinomas were histopathologically and immunohistochemically evaluated for β-catenin localization. Fourteen tumors (63.6%) that showed homogeneous low-grade morphology, preserving cell polarity, were found to harbor β-catenin protein on the cell membranes (M). Eight tumors exhibited regions of high-grade morphology among areas with low-grade morphology, and they were characterized by denser cell growth and loss of cell polarity. Among these 8 tumors, 4 (18.2%) showed cytoplasmic localization (C) of β-catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) β-catenin staining. Analysis of DNA obtained by microdissection demonstrated that all of 4 regions with C staining and 20 with M staining, as well as 17 samples of surrounding normal mucosa (S) had wild-type β-catenin. In contrast, all of 3 regions with N staining featured mutations (3 of 3=100%; N vs. C, P<0.05; N vs. M and N vs. S, P<0.001, Fisher's exact test) in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. In conclusion, β-catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis, in contrast to the case of colorectal cancers, in which mutations appear to occur in the early stages.
AB - Aberrant Wnt/β-catenin signaling caused by mutations in exon 3 of the β-catenin gene has been identified in a number of human malignancies, including stomach cancer. However, studies of mutation frequency have yielded conflicting results, and timing during progression remains largely unknown. In this study, we utilized an animal model to address this question. A total of 20 ACI male rats were treated with N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) in the drinking water and 22 induced differentiated adenocarcinomas were histopathologically and immunohistochemically evaluated for β-catenin localization. Fourteen tumors (63.6%) that showed homogeneous low-grade morphology, preserving cell polarity, were found to harbor β-catenin protein on the cell membranes (M). Eight tumors exhibited regions of high-grade morphology among areas with low-grade morphology, and they were characterized by denser cell growth and loss of cell polarity. Among these 8 tumors, 4 (18.2%) showed cytoplasmic localization (C) of β-catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) β-catenin staining. Analysis of DNA obtained by microdissection demonstrated that all of 4 regions with C staining and 20 with M staining, as well as 17 samples of surrounding normal mucosa (S) had wild-type β-catenin. In contrast, all of 3 regions with N staining featured mutations (3 of 3=100%; N vs. C, P<0.05; N vs. M and N vs. S, P<0.001, Fisher's exact test) in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. In conclusion, β-catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis, in contrast to the case of colorectal cancers, in which mutations appear to occur in the early stages.
UR - http://www.scopus.com/inward/record.url?scp=0345768487&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0345768487&partnerID=8YFLogxK
U2 - 10.1111/j.1349-7006.2003.tb01399.x
DO - 10.1111/j.1349-7006.2003.tb01399.x
M3 - Article
C2 - 14662019
AN - SCOPUS:0345768487
SN - 1347-9032
VL - 94
SP - 1046
EP - 1051
JO - Cancer science
JF - Cancer science
IS - 12
ER -
