NF-κB1, NF-κB2 and c-Rel differentially regulate susceptibility to colitis-associated adenoma development in C57BL/6 mice.
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.
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, UK.
Michael D
MD
Burkitt
Faculty of Medicine, University of Tripoli, Tripoli, Libya.
Abdalla F
AF
Hanedi
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, UK.
Carrie A
CA
Duckworth
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, UK.
Jonathan M
JM
Williams
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, UK.
Joseph M
JM
Tang
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, The University of Melbourne, Australia.
Lorraine A
LA
O'Reilly
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.|Department of Medical Biology, The University of Melbourne, Australia.
Tracy L
TL
Putoczki
Australian Centre for Blood Diseases, Monash University Central Clinical School, Melbourne, Australia.
Steve
S
Gerondakis
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, UK.
Rod
R
Dimaline
IBR-MRC Centre for Immune Regulation, College of Medicine and Dental Sciences, University of Birmingham, UK.
Jorge H
JH
Caamano
Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, UK.
D Mark
DM
Pritchard
D000236:Adenoma / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D015398:Signal Transduction
D016207:Cytokines; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; D020569:Proto-Oncogene Proteins c-rel; D016264:Dextran Sulfate; D001397:Azoxymethane
NF-κB; azoxymethane; colitis; colorectal cancer; dextran sulphate sodium; p68 c-Rel