Chemical-specific alterations in ras, p53, and β-catenin genes in hemangiosarcomas from B6C3F1 mice exposed to o-nitrotoluene or riddelliine for 2 years
Chemical-specific alterations in ras, p53, and β-catenin genes in hemangiosarcomas from B6C3F1 mice exposed to o-nitrotoluene or riddelliine for 2 years
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DOI：
10.1016/s0041-008x(03)00165-0
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发表时间：
2003-09-15
影响因子：
3.8
通讯作者：
Sills, RC
中科院分区：
文献类型：
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作者：
Hong, HL;Ton, TV;Sills, RC
在邻硝基甲苯和riddelliine的2年研究中，小鼠最突出的肿瘤病变是血管瘤。对15例邻硝基甲苯诱导的骨骼肌、皮下组织和肠系膜血管瘤，12例riddellin诱导的肝脏血管瘤和15例自发性皮下血管瘤进行ras、p53和β-连环蛋白基因的遗传改变检查。在15例邻硝基甲苯诱导的血管肉瘤中，有13例（87%）发现了至少一种基因的突变，其中11例（73%）发现了p53外显子5-8的错义突变。暴露于邻硝基甲苯的小鼠的15个血管瘤中有7个（47%）在外显子2剪接位点有缺失，或在β-连环蛋白基因中有较小的缺失。K-ras基因突变仅见于15例（7%）邻硝基甲苯诱发的血管瘤。与邻硝基甲苯研究相反，7/12（58%）的riddelime诱导的血管瘤有K-ras密码子12 GTT突变，免疫组化筛选时，9/12（75%）的恶性血管内皮细胞（血管瘤的起源细胞）中的p53蛋白染色强烈。Riddellime诱导的血管瘤对β-连环蛋白呈阴性。对照组小鼠的自发性血管瘤缺乏p53和β-连环蛋白表达以及ras突变。我们的数据表明，邻硝基甲苯诱导的血管瘤中的P53和β-连环蛋白突变以及riddelime诱导的血管瘤中的K-ras突变和p53蛋白表达最有可能是由于这些化学物质的遗传毒性作用而发生的。这也表明这些突变在B6 C3 F1（1）小鼠的相应血管瘤发病机制中起作用。(C)2003年爱思唯尔公司All rights reserved.
The most prominent neoplastic lesions in mice in the 2-year studies of o-nitrotoluene and riddelliine were hemangiosarcomas. Fifteen o-nitrotoluene-induced hemangiosarconnas of the skeletal muscle, subcutaneous tissue, and mesentery; 12 riddelliine-induced hemangiosarcomas of the liver; and 15 spontaneous subcutaneous hemangiosarcomas were examined for genetic alterations in ras, p53, and beta-catenin genes. Mutations in at least one of these genes were identified in 13 of 15 (87%) of the o-nitrotoluene-induced hemangiosarcomas with missense mutations in p53 exons 5-8 detected in 11 of 15 (73%) of these neoplasms. Seven of 15 (47%) hemangiosarcomas from mice exposed to o-nitrotoluene had deletions at exon 2 splice sites or smaller deletions in the beta-catenin gene. K-ras mutation was detected in only I of the 15 (7%) o-nitrotoluene-induced hemangiosarcomas. In contrast to the o-nitrotoluene study, 7/12 (58%) riddellime-induced hemangiosarcomas had K-ras codon 12 GTT mutations and, when screened by immunohistochemistry, 9/12 (75%) had strong staining for the p53 protein in malignant endothelial cells, the cells of origin of hemangiosarcomas. Riddellime-induced hemangiosarcomas were negative for the beta-catenin protein. Spontaneous hemangiosarcomas from control mice lacked both p53 and beta-catenin protein expression and ras mutations. Our data indicated that P53 and beta-catenin mutations in the o-nitrotoluene-induced hemangiosarcomas and K-ras mutations and p53 protein expression in riddellime-induced hemangiosarcomas most likely occurred as a result of the genotoxic effects of these chemicals. It also suggests that these mutations play a role in the pathogenesis of the respective hemangiosarcomas in B6C3F1(1) mice. (C) 2003 Elsevier Inc. All rights reserved.