NF-kappaB1, NF-kappaB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice
- Author(s)
- Burkitt, MD; Hanedi, AF; Duckworth, CA; Williams, JM; Tang, JM; O'Reilly, LA; Putoczki, TL; Gerondakis, S; Dimaline, R; Caamano, JH; Pritchard, DM;
- Details
- Publication Year 2015-07,Volume 236,Issue #3,Page 326-36
- Journal Title
- J Pathol
- Publication Type
- Journal Article
- Abstract
- NF-kappaB 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-kappaB signalling is an important regulator of these processes. In the stomach, it has also been demonstrated that signalling involving specific NF-kappaB proteins, including NF-kappaB1/p50, NF-kappaB2/p52, and c-Rel, differentially regulate the development of gastric pre-neoplasia. To investigate the effect of NF-kappaB 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-kappaB subunits in this model of colitis-associated carcinogenesis. NF-kappaB2/p52 is necessary for the development of colitis, whilst c-Rel-mediated signalling regulates colonic epithelial cell turnover following DNA damage.
- Publisher
- Wiley
- Research Division(s)
- Molecular Genetics Of Cancer; Inflammation
- PubMed ID
- 25727407
- Publisher's Version
- https://doi.org/10.1002/path.4527
- Open Access at Publisher's Site
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- Refer to copyright notice on published article.
Creation Date: 2015-09-02 03:35:44
Last Modified: 2015-09-03 03:42:00