o-Nitrotoluene-induced large intestinal tumors in B6C3F1 mice model human colon cancer in their molecular pathogenesis.
o-Nitrotoluene-induced large intestinal tumors in B6C3F1 mice model human colon cancer in their molecular pathogenesis.
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DOI：
10.1093/carcin/bgh044
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发表时间：
2003-10
期刊：
影响因子：
4.7
通讯作者：
R. Sills;H. Hong;G. Flake;C. Moomaw;N. Clayton;G. Boorman;J. Dunnick;T. Devereux
中科院分区：
文献类型：
--
作者：
R. Sills;H. Hong;G. Flake;C. Moomaw;N. Clayton;G. Boorman;J. Dunnick;T. Devereux
在国家毒理学计划之前的500项2年化学生物测定中，在B6 C3 F1小鼠中未观察到与化学品暴露相关的大肠肿瘤（盲肠癌）。最近完成的邻硝基甲苯研究提供了第一个盲肠肿瘤反应，并有机会评估与人类相关的癌基因和肿瘤抑制基因的形态和分子特征。形态学上，癌是腺体形成的肿瘤，内衬高柱状上皮细胞，细胞角蛋白20阳性，细胞角蛋白7阴性。使用免疫组织化学方法，在80%（8/10）的盲肠癌中检测到β-连环蛋白（Catnb编码）蛋白积聚，而在73%（8/11）的盲肠癌中分别检测到细胞周期蛋白D1和p53蛋白表达增加。腺瘤性息肉病蛋白在正常结肠和盲肠癌中的表达无差异。检查的所有肿瘤均在Catnb基因的外显子2（对应于人类的外显子3）中显示突变。p53突变在11个癌中的9个中被确定，并且全部在外显子7中。对K-ras基因的分析显示82%（9/11）的癌发生突变;所有癌在密码子10或12处都有特异性的G -> T颠换（Gly->瓦尔）。在小鼠大肠肿瘤中发现的癌症基因和蛋白质的改变包括激活信号转导途径的突变（K-ras和Catnb）和破坏细胞周期和绕过G（1）停滞的变化（p53，细胞周期蛋白D1）。这些改变，这是人类结肠癌的标志，可能有助于大肠癌的发病机制，在小鼠邻硝基甲苯暴露。
In the previous 500 2-year chemical bioassays within the National Toxicology Program, large intestinal tumors (cecal carcinomas) related to chemical exposure have not been observed in B6C3F1 mice. The recently completed o-nitrotoluene study provided the first cecal tumor response and an opportunity to evaluate the morphology and molecular profile of oncogenes and tumor suppressor genes that are relevant to humans. Morphologically, the carcinomas were gland-forming tumors lined by tall columnar epithelial cells that were positive for cytokeratin 20 and negative for cytokeratin 7. Using immunohistochemistry beta-catenin (encoded by Catnb) protein accumulation was detected in 80% (8/10) of the cecal carcinomas, while increased cyclin D1 and p53 protein expression was detected in 73% (8/11), respectively. There was no difference in adenomatous polyposis protein expression between normal colon and cecal carcinomas. All tumors examined exhibited mutations in exon 2 (corresponds to exon 3 in humans) in the Catnb gene. Mutations in p53 were identified in nine of 11 carcinomas, and all were in exon 7. Analysis of the K-ras gene revealed mutations in 82% (9/11) of carcinomas; all had specific G --> T transversions (Gly --> Val) at codons 10 or 12. The alterations in cancer genes and proteins found in the mouse large intestinal tumors included mutations that activate signal transduction pathways (K-ras and Catnb) and changes that disrupt the cell-cycle and bypass G(1) arrest (p53, cyclin D1). These alterations, which are hallmarks of human colon cancer, probably contributed to the pathogenesis of the large intestinal carcinomas in mice following o-nitrotoluene exposure.