Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice

Takuro Isoda, Yoshimichi Nakatsu, Kazumi Yamauchi, Jingshu Piao, Takashi Yao, Hiroshi Honda, Yusaku Nakabeppu, Teruhisa Tsuzuki

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)940-947
Number of pages8
JournalInternational journal of biological sciences
Volume10
Issue number8
DOIs
Publication statusPublished - Aug 23 2014

Fingerprint

abnormality
tumor
carcinogenesis
Carcinogenesis
Oxidative Stress
oxidative stress
mutation
neoplasms
mice
Mutation
Neoplasms
DNA Glycosylases
glycosylases
Catenins
Wnt Signaling Pathway
Adenomatous Polyposis Coli
Germ-Line Mutation
gene
adenoma
Adenine

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Applied Microbiology and Biotechnology
  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice. / Isoda, Takuro; Nakatsu, Yoshimichi; Yamauchi, Kazumi; Piao, Jingshu; Yao, Takashi; Honda, Hiroshi; Nakabeppu, Yusaku; Tsuzuki, Teruhisa.

In: International journal of biological sciences, Vol. 10, No. 8, 23.08.2014, p. 940-947.

Research output: Contribution to journalArticle

@article{6a4b1592f42d4baea3a5ecd725986d7b,
title = "Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice",
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.",
author = "Takuro Isoda and Yoshimichi Nakatsu and Kazumi Yamauchi and Jingshu Piao and Takashi Yao and Hiroshi Honda and Yusaku Nakabeppu and Teruhisa Tsuzuki",
year = "2014",
month = "8",
day = "23",
doi = "10.7150/ijbs.9241",
language = "English",
volume = "10",
pages = "940--947",
journal = "International Journal of Biological Sciences",
issn = "1449-2288",
publisher = "Ivyspring International Publisher",
number = "8",

}

TY - JOUR

T1 - Abnormality in Wnt signaling is causatively associated with oxidative stress-induced intestinal tumorigenesis in MUTYH-null mice

AU - Isoda, Takuro

AU - Nakatsu, Yoshimichi

AU - Yamauchi, Kazumi

AU - Piao, Jingshu

AU - Yao, Takashi

AU - Honda, Hiroshi

AU - Nakabeppu, Yusaku

AU - Tsuzuki, Teruhisa

PY - 2014/8/23

Y1 - 2014/8/23

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84906729442&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906729442&partnerID=8YFLogxK

U2 - 10.7150/ijbs.9241

DO - 10.7150/ijbs.9241

M3 - Article

C2 - 25170306

AN - SCOPUS:84906729442

VL - 10

SP - 940

EP - 947

JO - International Journal of Biological Sciences

JF - International Journal of Biological Sciences

SN - 1449-2288

IS - 8

ER -