Abstract
NF‐κB signalling is an important factor in the development of inflammation‐associated cancers. Mouse models of Helicobacter‐induced gastric cancer and colitis‐associated colorectal cancer have demonstrated that classical NF‐κB signalling is an important regulator of these processes. In the stomach, it has also been demonstrated that signalling involving specific NF‐κB proteins, including NF‐κB1/p50, NF‐κB2/p52, and c‐Rel, differentially regulate the development of gastric pre‐neoplasia. To investigate the effect of NF‐κB subunit loss on colitis‐associated carcinogenesis, we administered azoxymethane followed by pulsed dextran sodium sulphate to C57BL/6, Nfkb1−/−, Nfkb2−/−, and c‐Rel−/−mice. Animals lacking the c‐Rel subunit were more susceptible to colitis‐associated cancer than wild‐type mice, developing 3.5 times more colonic polyps per animal than wild‐type mice. Nfkb2−/− mice were resistant to colitis‐associated cancer, developing fewer polyps per colon than wild‐type mice (median 1 compared to 4). To investigate the mechanisms underlying these trends, azoxymethane and dextran sodium sulphate were administered separately to mice of each genotype. Nfkb2−/− mice developed fewer clinical signs of colitis and exhibited less severe colitis and an attenuated cytokine response compared with all other groups following DSS administration. Azoxymethane administration did not fully suppress colonic epithelial mitosis in c‐Rel−/− mice and less colonic epithelial apoptosis was also observed in this genotype compared to wild‐type counterparts. These observations demonstrate different functions of specific NF‐κB subunits in this model of colitis‐associated carcinogenesis. NF‐κB2/p52 is necessary for the development of colitis, whilst c‐Rel‐mediated signalling regulates colonic epithelial cell turnover following DNA damage. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Chronic idiopathic inflammatory bowel diseases, including Crohn’s colitis and ulcerative colitis, increase an individual’s risk of developing colorectal cancer in proportion to the extent and duration of the underlying inflammatory bowel disease [1,2,3,4]
Wild-type mice exhibited a modest clinical response to this regime. Their weight increased consistently following the first cycle of 0.5% w/v dextran sulphate sodium (DSS) [8% (± SEM 0.95)]; the dose was increased to 0.75% w/v DSS for subsequent cycles
Nfkb1−/− mice developed a similar pattern of clinical signs and area under the curve (AUC)
Summary
Chronic idiopathic inflammatory bowel diseases, including Crohn’s colitis and ulcerative colitis, increase an individual’s risk of developing colorectal cancer in proportion to the extent and duration of the underlying inflammatory bowel disease [1,2,3,4]. This suggests that chronic colonic inflammation is pivotal to the development of colon cancer, but the molecular mechanisms that influence an individual’s risk of developing colitis-associated colon cancer have not been fully established.
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