Sakamoto Katsumi, Tominaga Yohei, Yamauchi Kazumi, Nakatsu Yoshimichi, Sakumi Kunihiko, Yoshiyama Kaoru, Egashira Akinori, Kura Shinobu, Yao Takashi, Tsuneyoshi Masazumi, Maki Hisaji, Nakabeppu Yusaku, Tsuzuki Teruhisa
Departments of Medical Biophysics and Radiation Biology, Clinical Radiology, and Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Maidashi Higashi-ku, Fukuoka 812-8582, Japan.
Cancer Res. 2007 Jul 15;67(14):6599-604. doi: 10.1158/0008-5472.CAN-06-4802.
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 (11 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 KBrO(3), 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) in 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.
MUTYH是一种哺乳动物DNA糖基化酶，它通过切除与8-氧代鸟嘌呤相对的腺嘌呤以及与鸟嘌呤相对的2-羟基腺嘌呤来启动碱基切除修复，从而防止由氧化应激导致的G:C到T:A的颠换。最近，在易患隐性遗传性多发性结肠直肠腺瘤和癌且APC基因中G:C到T:A体细胞突变发生率增加的患者中发现了MUTYH的双等位基因种系突变。在本研究中，系统的组织学检查显示，MUTYH基因敲除小鼠（121只中有72只；59.5%）比野生型小鼠（109只中有38只；34.9%）发生了更多的自发肿瘤。与野生型小鼠（109只中无肠道肿瘤）相比，MUTYH基因敲除小鼠肠道肿瘤的发生率增加（121只小鼠中有10只出现11个肿瘤）具有统计学意义。在小肠中观察到2个腺瘤和7个腺癌，在结肠中发现了2个腺瘤但未发现癌。在用溴酸钾处理的MUTYH基因敲除小鼠中，小肠肿瘤的发生率显著增加。这些小鼠小肠中诱导产生的息肉平均数量为61.88（雄性为72.75，雌性为51.00），而野生型小鼠为0.85（雄性为0.50，雌性为1.00）。肿瘤主要发生在十二指肠和小肠（空肠）上部区域。我们得出结论，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突变与人类隐性遗传性结肠直肠腺瘤和癌之间的关联提供了实验证据。
