β-catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol
β-catenin mutation in rat colon tumors initiated by 1,2-dimethylhydrazine and 2-amino-3-methylimidazo[4,5-f]quinoline, and the effect of post-initiation treatment with chlorophyllin and indole-3-carbinol
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DOI：
10.1093/carcin/22.2.315
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发表时间：
2001-02-01
期刊：
影响因子：
4.7
通讯作者：
Dashwood, RH
中科院分区：
文献类型：
--
作者：
Blum, CA;Xu, MR;Dashwood, RH
致癌物2-氨基-3-甲基咪唑[4，5-f]喹啉（IQ）和1，2-二甲基肼（DMH）在大鼠中诱导结肠肿瘤，其含有β-连环蛋白的突变，但突变模式与在人类结肠癌中发现的不同。在这两个物种中，突变影响β-连环蛋白的糖原合成酶激酶-3 β共有区，但尽管它们直接取代人类结肠癌中的关键Ser/Thr磷酸化位点，但在大鼠肿瘤中大多数突变聚集在Ser 33周围。两种膳食植物化学物质，叶绿酸和吲哚-3-甲醇，在启动后给予，改变了IQ和DMH诱导的大鼠结肠肿瘤中β-连环蛋白突变的模式。具体地说，在给予致癌物加调节剂的组中，17/39（44%）的β-连环蛋白突变在密码子37、41和45中，并直接取代了关键的Ser/Thr残基，如在人结肠癌中所见.来自单独给予致癌物的组的肿瘤中没有一个在这些密码子中具有突变.有趣的是，许多取代β-连环蛋白中关键Ser/Thr残基的突变来自给予DMH和0.001%叶绿酸的单一组，其中与仅给予DMH的组相比，观察到结肠肿瘤多样性的统计学显著增加。与含有野生型β-连环蛋白的肿瘤相比，这些肿瘤具有细胞周期蛋白DI、c-myc和c-jun mRNA的显著过表达，并且c-Myc和c-Jun蛋白质强烈升高。结果表明，大鼠结肠肿瘤中β-连环蛋白突变的模式可以受到暴露于起始后施用的膳食植物化学物质的影响，其机制可能与β-catenin/Tcf/Lef靶基因表达的改变有关。
Carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 1,2-dimethylhydrazine (DMH) induce colon tumors in the rat that contain mutations in beta -catenin, but the pattern of mutation differs from that found in human colon cancers. In both species, mutations affect the glycogen synthase kinase-3 beta consensus region of beta -catenin, but whereas they directly substitute critical Ser/Thr phosphorylation sites in human colon cancers, the majority of mutations cluster around Ser33 in the rat tumors. Two dietary phytochemicals, chlorophyllin and indole-3-carbinol, given post-initiation, shifted the pattern of beta -catenin mutations in rat colon tumors induced by IQ and DMH. Specifically, 17/39 (44%) of the beta -catenin mutations in groups given carcinogen plus modulator were in codons 37, 41 and 45, and substituted critical Ser/Thr residues directly, as seen in human colon cancers, None of the tumors from groups given carcinogen alone had mutations in these codons. Interestingly, many of the mutations that substituted critical Ser/Thr residues in beta -catenin were from a single group given DMH and 0.001% chlorophyllin, in which a statistically significant increase in colon tumor multiplicity was observed compared with the group given DMH only. These tumors had marked over-expression of cyclin DI, c-myc and c-jun mRNA and c-Myc and c-Jun proteins were strongly elevated compared with tumors containing wild-type beta -catenin, The results indicate that the pattern of beta -catenin mutations in rat colon tumors can be influenced by exposure to dietary phytochemicals administered postinitiation, and that the mechanism might involve the altered expression of beta -catenin/Tcf/Lef target genes.