Isoda Takuro, Nakatsu Yoshimichi, Yamauchi Kazumi, Piao Jingshu, Yao Takashi, Honda Hiroshi, Nakabeppu Yusaku, Tsuzuki Teruhisa
1. Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan, ; 2. Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
1. Department of Medical Biophysics and Radiation Biology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
Int J Biol Sci. 2014 Aug 23;10(8):940-7. doi: 10.7150/ijbs.9241. eCollection 2014.
MUTYH is a DNA glycosylase that excises adenine paired with 8-oxoguanine to prevent mutagenesis in mammals. Biallelic germline mutations of MUTYH have been found in patients predisposed to a recessive form of familial adenomatous polyposis (MAP: MUTYH-associated polyposis). We previously reported that Mutyh-deficient mice showed a high susceptibility to spontaneous and oxidative stress-induced intestinal adenoma/carcinoma. Here, we performed mutation analysis of the tumor-associated genes including Apc, Ctnnb1, Kras and Trp53 in the intestinal tumors of Mutyh-deficient mice. In the 62 tumors, we identified 25 mutations in Apc of 18 tumors and 36 mutations in Ctnnb1 of 36 tumors. Altogether, 54 out of the 62 tumors (87.1%) had a mutation in either Apc or Ctnnb1; no tumor displayed mutations simultaneously in the both genes. Similar to MAP, 60 out of 61 mutations (98.3%) were identified as G:C to T:A transversions of which 85% occurred at either AGAA or TGAA sequences. Immunohistochemical analyses revealed the accumulation of β-catenin in the nuclei of tumors. No mutation was found in either Kras or Trp53 in the tumors. These results indicate that the uncontrolled activation of Wnt signaling pathway is causatively associated with oxidative stress-induced intestinal tumorigenesis in the Mutyh-deficient mice.
MUTYH是一种DNA糖基化酶，可切除与8-氧代鸟嘌呤配对的腺嘌呤，以防止哺乳动物发生诱变。在易患隐性家族性腺瘤性息肉病（MAP：MUTYH相关息肉病）的患者中发现了MUTYH的双等位基因种系突变。我们之前报道过，Mutyh基因缺陷的小鼠对自发性和氧化应激诱导的肠道腺瘤/癌高度敏感。在此，我们对Mutyh基因缺陷小鼠肠道肿瘤中包括Apc、Ctnnb1、Kras和Trp53在内的肿瘤相关基因进行了突变分析。在62个肿瘤中，我们在18个肿瘤的Apc中鉴定出25个突变，在36个肿瘤的Ctnnb1中鉴定出36个突变。总共62个肿瘤中有54个（87.1%）在Apc或Ctnnb1中发生了突变；没有肿瘤同时在这两个基因中显示出突变。与MAP相似，61个突变中有60个（98.3%）被鉴定为G:C到T:A的颠换，其中85%发生在AGAA或TGAA序列处。免疫组织化学分析显示β-连环蛋白在肿瘤细胞核中积累。在肿瘤的Kras或Trp53中均未发现突变。这些结果表明，Wnt信号通路的失控激活与Mutyh基因缺陷小鼠中氧化应激诱导的肠道肿瘤发生有因果关系。
