Oxidative stress-induced intestinal tumorigenesis in mice with targeted disruption of the Mutyh gene

Abstract

Oxygen radicals are produced through normal cellular metabolism, and the formation of such radicals is further enhanced by exposure to either ionizing radiation or various chemicals. The oxygen radicals attack DNA and its precursor nucleotides, and consequently induce various oxidized forms of bases in DNA within normally growing cells. Among such modified bases, 8-oxo-7, 8-dihydroguanine (8-oxoG) and 2-hydroxyadenine (2-OH-A) are highly mutagenic lesions, if not repaired. MUTYH is a DNA glycosylase that excises adenine or 2-OH-A incorporated opposite either 8-oxoG or guanine, respectively, thus considered to prevent G:C to T:A transversions in mammalian cells. The Mutyh-deficient mice showed a marked predisposition to spontaneous tumorigenesis in various tissues when examined at 18 months of age. The incidence of adenoma/carcinoma in the intestine significantly increased in Mutyh-deficient mice, as compared with wild-type mice. This high susceptibility of the mutant mice to intestinal tumor-development was well correlated with the condition observed in MAP (MUTYH-associated polyposis) patients. We performed mutation analysis of the tumor-associated genes amplified from the intestinal tumors developed in four mutant mice that had been treated with KBrO₃. Many tumors had G:C to T:A transversions in either Apc or Ctnnb1. No mutations were found in either k-ras (exon 2) or Trp53 (exon 5-8). Our findings indicate that the abnormality in the Wnt signaling pathway is causatively associated with oxidative stress-induced tumorigenesis in the small intestines of the Mutyh-deficient mice.