Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment.
Chronic inflammation has been associated with increased risk of developing cancer. The transcription factor NF-E2-related factor 2 (Nrf2) controls the expression of numerous antioxidative enzymes that have been shown to attenuate acute inflammation. The present study investigated the role of Nrf2 genotype in modulating inflammation-promoted colorectal tumorigenesis. Nrf2 wild-type (WT) and Nrf2-deficient (N0) mice were administered a single dose of azoxymethane followed by a 1-week dose of drinking water with or without 1% dextran sulfate sodium (DSS). Aberrant crypt foci were counted 3 weeks after the cessation of DSS treatment. DSS treatment significantly increased numbers of aberrant crypt foci in N0 mice, but not WT mice. The extent of inflammation over the course of DSS treatment was analyzed in both genotypes. Histological analysis of colon sections revealed that N0 mice had markedly increased inflammation and mucosal damage when compared to WT mice beginning on Day 6 of DSS treatment. Although similar levels of inflammatory and oxidative damage biomarkers were evident in colons from WT and N0 mice at the start of DSS treatment, increased colonic proinflammatory cytokine mRNA transcript levels, myeloperoxidase activity and 3-nitrotyrosine immunoreactivity were observed on Day 6 of DSS treatment in N0 mice, but not WT mice. Additionally, DSS treatment resulted in increased lipid peroxidation and loss of aconitase activity in N0 mice, but not WT mice, reflecting increased oxidative damage in colons from N0 mice. Taken together, these results clearly illustrate the role of Nrf2 in regulating an adaptive response that protects against early-phase inflammation-mediated tumorigenesis.
Osburn
William O
WO
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Karim
Baktiar
B
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.|Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD.
Dolan
Patrick M
PM
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
Liu
Guosheng
G
Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD.
Yamamoto
Masayuki
M
Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance and JST-ERATO Environmental Response Project, University of Tsukuba, Tsukuba, Japan.
Huso
David L
DL
Department of Molecular and Comparative Pathobiology, School of Medicine, Johns Hopkins University, Baltimore, MD.
Kensler
Thomas W
TW
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD.
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D015415:Biomarkers; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003106:Colon / Q000187:drug effects / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects
D015415:Biomarkers; D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016264:Dextran Sulfate; D001397:Azoxymethane