Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice
✍ Scribed by Jie Liao; Darren N. Seril; Gary G. Lu; Meng Zhang; Shinya Toyokuni; Allison L. Yang; Guang-Yu Yang
- Book ID
- 102944120
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 577 KB
- Volume
- 47
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.20427
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✦ Synopsis
Abstract
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. © 2008 Wiley‐Liss, Inc.