Ulcerative Colitis-Induced Carcinoma Development in NADPH-Oxidase GP91 Knock-Out Mice
P Dhakras, J Liao, AL Yang, GY Yang. Northwestern University, Chicago, IL
Background: GP91phox is the catalytic domain of the leukocyte NADPH oxidase responsible for superoxide production. Superoxide can cause DNA damage either by itself or by combining with NO to form the highly reactive species peroxynitrite, which may lead to mutation and genetic instability. In order to study the role of inflammation-caused oxidative stress in ulcerative colitis (UC)-induced colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced UC-carcinogenesis model in gp91-/-deficient mice.
Design: Female wild-type C57BL/6 (gp91+/+) and gp91-/- mice were administered 0.7% DSS (w/v) through the drinking fluid for 11 DSS cycles and fed 2-fold iron enriched diet.Swiss-rolled colonic specimens were collected and processed for histopathologic and immununohistopathologic analysis for inflammation, dysplasia and carcinoma.
Results: Colorectal inflammation and mucosal ulceration of mild severity were observed in both gp91+/+ and gp91-/- mice. Twelve of 24 (50%) gp91+/+ mice developed colorectal tumors after 11 DSS cycles treatment, with a tumor multiplicity of 1.12 0.17 (mean SE). In gp91-/- mice, significantly decreased tumor development was observed.Five of 21 (23.9%) mice developed colorectal tumors and the mean tumor number per gp91-/- mouse was 1.0 0.0. Histopathologically, the tumors were confirmed to be well-differentiated tubular and mucinous adenocarcinomas. Nitrotyrosine, an indicator of peroxynitrite-caused protein modification, was detectable by immunohistochemistry in inflammatory cells and epithelial cells of the colon ingp91+/+ and gp91-/-mice, and showed that there was significant decrease in staining intensity and number of nitrotyrosine-positive cells in gp91-/- mice.
Conclusions: These results suggest that the leukocyte NADPH oxidase(GP91phox) is a key enzyme involved in inflammation-caused nitro-oxidative stress and carcinogenesis in this model system. These results provide important evidence on the relationship between inflammation, leukocyte NADPH oxidase, oxidative stress and carcinogenesis.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 217, Wednesday Morning