The molecular analysis of carcinogenesis in inflamed colon by gpt transgenic mice.

患有炎症性肠病(IBD)的人患胃肠道癌症的风险增加。在这里，我们测试了慢性炎症可能引发突变的可能性。为此，我们使用了自发发生肠道炎症的IL-10；+/+&gt；缺陷(IL-10；-/-&gt；)小鼠，结合了转基因gpt基因和红色gam基因(gpt^+IL-10；-/-&gt；)，这是一个特征良好的突变报告基因。Gpt^+IL-10^&lt；+/+&gt；小鼠结肠总突变频率约为正常gpt^+IL-10^&lt；+/+&gt；小鼠的5倍。在G：C到A：T转换的特殊情况下，gpt^+IL-10^&lt；-/-&gt；小鼠的突变频率是对照组的4.1倍。有趣的是，微小的删除和插入的频率也显著增加(10倍)。大多数缺失或插入突变发生在短串联序列的单调碱基序列或相邻重复序列中。相比之下，通过缺失红色GAM转基因中存在的SPI标记检测到的大片段缺失的频率在小鼠品系之间是相似的。最后，作为对照，在非炎症组织中，如肝脏，gpt^+IL-10^&lt；+/+&gt；小鼠与gpt^+IL-10^&lt；+/+&gt；小鼠的突变频率相似。我们的数据表明，结肠中的慢性炎症环境促进了突变的产生。

Individuals with inflammatory bowel disease (IBD) are at increased risk of developing gastrointestinal cancer. Here, we have tested the possibility that chronic inflammation could trigger mutations. For this, we have used IL-10^<+/+>deficient (IL-10^<-/->) mice, which spontaneously develop intestinal inflammation, in combination with a transgenic gpt gene and red gam gene (gpt^+IL-10^<-/->), which is a well-characterized mutation reporter locus. The total mutation frequency in the colon of gpt^+IL-10^<+/+>mice was about five times higher than that in normal gpt^+IL-10^<+/+>mice. In the particular case of G : C to A : T transitions, the frequency of mutations in gpt^+IL-10^<-/-> mice was 4.1 times higher than that in control mice. Interestingly, the frequency of small deletions and insertions was also strikingly increased (10 times). The majority of the deletion or insertion mutations were observed in the monotonous base runs or adjacent repeats of short tandem sequences. In contrast, the frequency of large deletions, detected by loss of the Spi marker present in the red gam transgene, was similar among the mouse strains. Finally, as a control, the mutation frequency in non-inflamed tissues, such as the liver, were similar between gpt^+IL-10^<+/+> mice and gpt^+ IL-10^<+/+> mice. Our data demonstrate that the chronic inflammatory environment in the colon promotes the generation of mutations.