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Int J Biol Sci 2014; 10(8):940-947. doi:10.7150/ijbs.9241

Research Paper

Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice

Takuro Isoda1, 2, Yoshimichi Nakatsu1, Kazumi Yamauchi1, Jingshu Piao1, Takashi Yao3, Hiroshi Honda2, Yusaku Nakabeppu4, Teruhisa Tsuzuki1 ✉

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,
3. Department of Human Pathology, School of Medicine, Juntendo University, Tokyo, Japan,
4. Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan,

Abstract

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.

Keywords: MAP, DNA repair, oxidative DNA damage, Wnt signaling pathway, mutagenesis

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How to cite this article:
Isoda T, Nakatsu Y, Yamauchi K, Piao J, Yao T, Honda H, Nakabeppu Y, Tsuzuki T. Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice. Int J Biol Sci 2014; 10(8):940-947. doi:10.7150/ijbs.9241. Available from http://www.ijbs.com/v10p0940.htm