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Relationship between activation of beta-catenin pathway and expression of inflamatory enzymes in colon carcinogenesis in experimental animals

实验动物结肠癌发生过程中β-catenin通路激活与炎症酶表达的关系

基本信息

批准号：
12670225
负责人：
TAKAHASHI Mami
金额：
$ 2.11万
依托单位：
National Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670225/
关键词：
Colon cancer Beta-catenin iNOS COX-2 K-ras Rat Mouse INOS

项目摘要

In this study, the relation between β-catenin alteration and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was examined in AOM-induced rat colon carcinogenesis. K-ras gene mutations were also investigated. Mutation analysis by PCR-single strand conformation polymorphism method and direct sequencing demonstrated the β-catenin gene to be frequently mutated from the stage of dysplastic aberrant crypt foci(ACF),the early stage of colon carcinogenesis. K-ras was frequently mutated in hyperplastic ACF, indicating that Kras may play an important role in the formation of ACF. Immunohistochernical staining showed alteration of cellular localization of β-catenin in all dysplastic ACF, adenomas and adenocarcinomas examined. iNOS expression was also observed in most of these lesions in which β-catenin alterations were observed. Neither iNOS expression nor β-catenin alterations were observed in any hyperplastic ACF. COX-2 expression in stromal elements was found even in normal colon mucosa, and increased in adenomas and adenocarcinomas, while epithelial cells were only positive in large adenocarcinomas. These results show that β-catenin alterations may be related to induction of iNOS expression, these being early events in AOM-induced colon tumorigenesis which may play important roles in causing dysplastic changes. Mutations in the p-catenin gene were also very frequently found in mouse colon tumors induced by AOM, while K-ras mutations were rare, suggesting that K-ras activation may be not essential for tumor development. However, in a cell culture system, transfection of the K-ras gene with an activating mutation enhanced iNOS expression induced by IL-lβ and LPS. Therefore, K-ras is also suggested to play an important role in colon tumorigenesis by enhancing iNOS expression.

本研究探讨AOM诱导大鼠结肠癌过程中β-catenin的变化与诱导型一氧化氮合酶（iNOS）和环氧合酶（考克斯）-2表达的关系。K-ras基因突变也进行了调查。PCR-单链构象多态性分析和直接测序分析表明，β-catenin基因在结肠癌发生的早期即异型增生异常隐窝灶（ACF）阶段发生突变。K-ras基因在ACF中的突变频率较高，提示K-ras基因在ACF的形成中起重要作用。免疫组织化学染色显示β-catenin在所有异型增生ACF、腺瘤和腺癌中的细胞定位改变。在大多数观察到β-catenin改变的病变中也观察到iNOS表达。在任何增生性ACF中均未观察到iNOS表达或β-catenin改变。考克斯-2在正常结肠粘膜中也有表达，在腺瘤和腺癌中表达增加，而上皮细胞仅在大腺癌中表达。这些结果表明，β-catenin的改变可能与诱导iNOS的表达有关，这些是AOM诱导的结肠肿瘤发生的早期事件，可能在引起异型增生变化中起重要作用。在AOM诱导的小鼠结肠肿瘤中也经常发现p-catenin基因的突变，而K-ras基因的突变是罕见的，这表明K-ras基因的激活可能不是肿瘤发展所必需的。然而，在细胞培养系统中，转染具有激活突变的K-ras基因增强IL-1 β和LPS诱导的iNOS表达。因此，K-ras基因可能通过增强iNOS的表达而在结肠肿瘤的发生中发挥重要作用。