Overexpression of MTH1 and OGG1 proteins in ulcerative colitis-associated carcinogenesis.

Oxidative stress, demonstrated by an accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG), results in DNA damage, which is normally repaired by base excision repair enzymes including 8-OHdG DNA glycosylase (OGG1) and human MutY homolog (MUTYH), in addition to nucleotide pool sanitizing enzymes including MutT Homolog 1 (MTH1). Abnormalities of this repair system are present in various cancer types. The present study aimed to elucidate the clinicopathological significance of altered expression levels of inducible nitric oxide synthase (iNOS), 8-OHdG, OGG1, MTH1 and MUTYH in ulcerative colitis (UC) and UC-associated neoplasms. Immunohistochemical staining for these markers and p53 in 23 cases of UC-associated neoplasm (Group A, 14 carcinomas and nine dysplasias), 16 cases of UC without neoplasm (Group B) and 17 cases of normal colon specimens (Group C) was performed. Mutation analyses was conducted for KRAS proto-oncogene, GTPase (K-ras), tumor protein P53 (TP53) and isocitrate dehydrogenase (NADP (+)) 1, cytosolic (IDH1) genes. Immunohistochemically, the iNOS, 8-OHdG, OGG1 and MTH1 expression levels were increased in Groups A and B compared with Group C. The OGG1 and MTH1 expression levels in Group A were also increased compared with Group B. Group A and Group B exhibited increased cytoplasmic expression and decreased nuclear expression of MUTYH compared with Group C. Mutations of K-ras and TP53 were detected in 2/21 (9.5%) and 10/22 (45.5%) cases of Group A, respectively. IDH1 mutation was not detected in any cases. These findings suggest that, as a response to oxidative damage, OGG1 and MTH1 may be upregulated in UC through an inflammatory condition that progresses to cancer formation. Persisting oxidative damage stress may play a role in the pathogenesis of UC-associated tumors.