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NF‐κB1, NF‐κB2 and c‐Rel differentially regulate susceptibility to colitis‐associated adenoma development in C57BL/6 mice

Burkitt, M D; Hanedi, A F; Duckworth, C A; Williams, J M; Tang, J M; O'Reilly, L A; Putoczki, T L; Gerondakis, S; Dimaline, R; Caamaño, J H; Pritchard, D M

Authors

M D Burkitt

A F Hanedi

C A Duckworth

J M Williams

J M Tang

L A O'Reilly

T L Putoczki

S Gerondakis

R Dimaline

J H Caamaño

D M Pritchard



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.

Citation

Burkitt, M. D., Hanedi, A. F., Duckworth, C. A., Williams, J. M., Tang, J. M., O'Reilly, L. A., …Pritchard, D. M. (2015). NF‐κB1, NF‐κB2 and c‐Rel differentially regulate susceptibility to colitis‐associated adenoma development in C57BL/6 mice. Journal of Pathology, 236(3), 326-336

Journal Article Type Article
Acceptance Date Feb 23, 2015
Publication Date Apr 21, 2015
Deposit Date Sep 6, 2018
Publicly Available Date Sep 6, 2018
Journal Journal of Pathology
Print ISSN 0022-3417
Publisher Pathological Society of Great Britain and Ireland
Peer Reviewed Peer Reviewed
Volume 236
Issue 3
Pages 326-336
Public URL https://rvc-repository.worktribe.com/output/1401171

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