Decreased susceptibility of chronic ulcerative colitis-induced carcinoma development in NADPH-oxidase gp91-deficient mice

Abstract

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GP91^phox 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 UC-associated colorectal carcinogenesis, the development of colorectal carcinoma was studied using the DSS-induced and iron-enhanced model of chronic UC-induced carcinogenesis in gp91-deficient mice. 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. Colorectal inflammation and mucosal ulceration of mild severity were observed in both gp91^+/+ and gp91^-/- mice. Twelve out of 24 (50%) gp91^+/+ mice developed colorectal tumors after 11 DSS cycles, with a tumor multiplicity of 1.12 ± 0.17 (mean ± SE). In gp91^-/- mice, significantly decreased tumor development was observed that five out 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 in gp91^+/+ and gp91^-/- mice, and showed that there were significantly decrease in staining intensity and number of nitrotyrosine-positive cells in gp91^-/- mice. These results suggest that the leukocyte NADPH oxidase(GP91^phox) is a key enzyme involved in inflammation-induced nitro-oxidative stress and UC-associated carcinogenesis in this model system. These results provide important evidence on the relationship between inflammation-caused oxidative stress, leukocyte NADPH oxidase, and carcinogenesis. (supported by NIH R01 CA104741).