Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice.
Ogg1 DNA repair enzyme recognizes and excises oxidative stress-caused 8-hydroxyl-deoxyguanosine (8-OHdG) from GC base-pairs. Ogg1 knockout mice are phenotypically normal, but exhibit elevated levels of 8-OHdG in nuclear and mitochondrial DNA, as well as moderately elevated mutagenesis and spontaneous lung tumors and UV-induced skin tumors. To elucidate the mechanistic role of inflammation-caused oxidative stress in carcinogenesis, the development of chronic ulcerative colitis (UC)-induced carcinoma in Ogg1 knockout mice was studied using a dextran sulfate sodium (DSS)-induced UC model without the use of a carcinogen. Ogg1 (-/-), Ogg1 (+/-), and wild type C57BL/6 mice were subjected to long-term, cyclic DSS treatment to induce chronic UC and carcinogenesis. In wild type C57BL/6 control mice after 15 cycles of DSS treatment, colorectal adenocarcinoma incidence was 24.1% (7/29 mice), with a tumor volume of 27.9 +/- 5.2 mm(3). Ogg1 (-/-) mice showed significantly increased adenocarcinoma development in the colon with a tumor incidence of 57.1% (12 of 21 mice, P < 0.05) and a tumor volume of 35.1 +/- 6.1 mm(3). Ogg1 mice (+/-) also exhibited significantly increased tumor development in the colon with a tumor incidence of 50.0% (13/26 mice) and a tumor volume of 29.1 +/- 7.2 mm(3). Histopathologic analyses revealed that colorectal tumors were well-differentiated tubular adenocarcinomas or mucinous carcinoma and adjacent colonic mucosa showed mild to moderate chronic UC. Using immunohistochemical approaches, Ogg1 (-/-) and (+/-) mice exhibited similar numbers and staining intensities of macrophages in UC areas as seen in Ogg1 (+/+) mice, but markedly increased numbers and staining intensities of 8-OHdG positive inflammatory and epithelial cells. These results provide important evidence on the relationship between inflammation-caused oxidative stress, DNA repair enzyme Ogg1, and carcinogenesis.
Liao
Jie
J
Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Seril
Darren N
DN
Lu
Gary G
GG
Zhang
Meng
M
Toyokuni
Shinya
S
Yang
Allison L
AL
Yang
Guang-Yu
GY
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001835:Body Weight; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics*; D003093:Colitis, Ulcerative / Q000150:complications*; D045647:DNA Glycosylases / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress
D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D003849:Deoxyguanosine