Altered expression of MUTYH and an increase in 8-hydroxydeoxyguanosine are early events in ulcerative colitis-associated carcinogenesis.
8-Hydroxy-guanine (8-OH-G) mismatches readily with adenine residues, leading to a G : C to T : A transversion mutation. The human mutY homologue (MUTYH) excises adenine misincorporated opposite 8-OH-G during replication and suppresses mutations caused by reactive oxygen species. We defined the expression of 8-hydroxydeoxyguanosine (8-OHdG) and MUTYH in ulcerative colitis (UC)-associated neoplasia by immunohistochemistry and compared this with expression in UC patients without neoplasia and patients unaffected by UC. We also performed mutation analyses for MUTYH and K-ras. 8-OHdG was expressed more intensely in the mucosa of UC-associated neoplasia and UC without neoplasm than in the mucosa unaffected by UC. Immunohistochemistry with two different types of MUTYH antibody showed that UC-associated neoplasia and UC without neoplasia exhibited strong cytoplasmic expression and attenuated nuclear expression of MUTYH when compared with patients unaffected by UC. No pathological MUTYH mutations were detected in any of the UC-associated neoplasia cases. However, K-ras mutation was detected in two cases, one of which showed G : C to T : A transversion mutation and attenuated nuclear staining of MUTYH. In conclusion, inflamed mucosa of UC is exposed to oxidative damage. An increase in cytoplasmic MUTYH, rather than its mutation, may contribute to the promotion of carcinogenesis in UC.
Gushima
Masaki
M
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Hirahashi
Minako
M
Matsumoto
Takayuki
T
Fujita
Kouhei
K
Fujisawa
Ritsuko
R
Mizumoto
Kazuhiro
K
Nakabeppu
Yusaku
Y
Iida
Mitsuo
M
Yao
Takashi
T
Tsuneyoshi
Masazumi
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000369:Aged, 80 and over; D002467:Cell Nucleus / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003106:Colon; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D045647:DNA Glycosylases / Q000032:analysis / Q000235:genetics*; D004252:DNA Mutational Analysis; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018709:Statistics, Nonparametric; D055815:Young Adult
D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D003849:Deoxyguanosine