MUTYH-null mice are susceptible to spontaneous and oxidative stress-induced intestinal tumorigenesis
MUTYH-null mice are susceptible to spontaneous and oxidative stress-induced intestinal tumorigenesis
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DOI：
10.1158/0008-5472.can-06-4802
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Tsuzuki, Teruhisa
中科院分区：
文献类型：
--
作者：
Sakamoto, Katsumi;Tominaga, Yohei;Tsuzuki, Teruhisa
MUTYH 是一种哺乳动物 DNA 糖基化酶，通过切除与 8-氧代鸟嘌呤相对的腺嘌呤和与鸟嘌呤相对的 2-羟基腺嘌呤来启动碱基切除修复，从而防止氧化应激引起的 G:C 到 T:A 颠换。最近，在易患隐性遗传性多发性结直肠腺瘤和癌的患者中发现了 MUTYH 的双等位基因种系突变，并且 APC 基因中 G:C 到 T:A 体细胞突变的发生率增加。在目前的研究中。系统组织学检查显示，MUTYH 缺失小鼠（121 只中的 72 只：59.5%）比野生型（109 只中的 38 只；34.9%）产生更多的自发性肿瘤。与野生型小鼠（109 只小鼠中没有肠道肿瘤）相比，MUTYH 缺失小鼠（121 只小鼠中的 10 只小鼠中有 10 只出现肿瘤）肠道肿瘤发生率增加具有统计学意义。小肠中发现2个腺瘤和7个腺癌，结肠中发现2个腺瘤但没有发现癌。在用 KBrO3 治疗的 MUTYH 缺失小鼠中，小肠肿瘤的发生率急剧增加。这些小鼠小肠中诱导的息肉平均数量为 61.88 个（雄性，72.75 个；雌性，51.00 个），而野生型小鼠为 0.85 个（雄性，0.50 个；雌性，1.00 个）。肿瘤主要发生在十二指肠和（空肠）小肠的上部区域。我们得出的结论是，MUTYH 抑制哺乳动物的自发肿瘤发生，从而为双等位基因种系 MUTYH 突变与隐性形式的人类遗传性结直肠腺瘤和癌之间的关联提供了实验证据。
MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study. a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121: 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (I I tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma.