Nrf2 inhibits colitis-promoted colorectal tumorigenesis by modulating colonic inflammation

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Chronic colitis has been associated with an increased risk of developing colorectal cancer. This risk increases with duration of colitis presumably due to an accumulation of inflammatory oxidative damage. The transcription factor NF-E2-related factor 2 (Nrf2), controls the expression of a number of antioxidative enzymes and the Nrf2adaptive response has been shown to be effective in reducing inflammation and inflammatory damage in acute inflammation animal models. The present study investigated the role of Nrf2 genotype in modulating inflammation-promoted colorectal tumorigenesis. Nrf2 wild-type (WT) and Nrf2 disrupted (N0) mice were administered a single dose of azoxymethane (7.5 mg/kg, i.p.) followed by a one-week dose of drinking water containing vehicle or dextran sulfate sodium (1%, p.o., DSS) and aberrant crypt foci were counted three weeks following the cessation of DSS treatment. DSS treatment resulted in significantly increased numbers of aberrant crypt foci in N0 mice, but not WT mice, suggesting that WT mice were resistant to DSS inflammation-promoted preneoplastic lesion formation at this dose and schedule. Therefore, inflammation over the course of DSS treatment was analyzed in both genotypes. Diarrhea was present in all N0 mice by day six of DSS treatment while diarrhea was absent in WT mice. Histological analysis of colon sections revealed that N0 mice had markedly increased inflammation and mucosal damage compared to WT mice beginning on day six of DSS treatment. Colons were then analyzed for biomarkers of inflammation and oxidative damage on day six of DSS treatment. Although similar levels of inflammatory and oxidative damage biomarkers were demonstrated in WT and N0 colons at the start of DSS treatment, increased colonic nitrotyrosine immunohistochemical staining and myeloperoxidase activity on day six of DSS treatment was demonstrated in N0 mice, but not WT mice, suggesting increased inflammation in N0 colons during DSS treatment while WT mice were resistant to DSS-mediated inflammation. Additionally, DSS treatment resulted in increased colonic lipid peroxidation and loss of aconitase activity in N0 mice, but not WT mice, representing increased oxidative damage in N0 colons. Taken together, these results clearly illustrate the role of Nrf2 in regulating an adaptive response attenuating colorectal inflammation and subsequently leading to protection against inflammation-mediated tumorigenesis. Supported by CA94076, ES03819, K01RR021362 and T32ES07141.