Abnormality in Wnt Signaling is Causatively Associated with Oxidative Stress-Induced Intestinal Tumorigenesis in MUTYH-Null Mice
| Autor: | Hiroshi Honda, Takashi Yao, Yoshimichi Nakatsu, Kazumi Yamauchi, Teruhisa Tsuzuki, Takuro Isoda, Yusaku Nakabeppu, Jingshu Piao |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Beta-catenin Carcinogenesis Adenomatous Polyposis Coli Protein DNA repair medicine.disease_cause Applied Microbiology and Biotechnology oxidative DNA damage DNA Glycosylases Familial adenomatous polyposis Wnt signaling pathway Mice Germline mutation MUTYH Intestinal Neoplasms medicine Animals Genetic Predisposition to Disease Molecular Biology beta Catenin Ecology Evolution Behavior and Systematics Mutation biology Cell Biology medicine.disease Molecular biology Mice Inbred C57BL Oxidative Stress MAP ras Proteins biology.protein Cancer research Female KRAS Tumor Suppressor Protein p53 mutagenesis Research Paper Developmental Biology |
| Zdroj: | International Journal of Biological Sciences |
| ISSN: | 1449-2288 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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