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

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.

• Authors: Michael D Burkitt, Abdalla F Hanedi, Carrie A Duckworth, Jonathan M Williams, Joseph M Tang, Lorraine A O'Reilly, Tracy L Putoczki, Steve Gerondakis, Rod Dimaline, Jorge H Caamano, D Mark Pritchard
• Journal: The Journal of pathology (J Pathol) Vol. 236 Issue 3 Pg. 326-36 (Jul 2015) ISSN: 1096-9896 [Electronic] England
• PMID: 25727407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Chemical References

• Cytokines
• NF-kappa B p50 Subunit
• NF-kappa B p52 Subunit
• Proto-Oncogene Proteins c-rel
• Dextran Sulfate
• Azoxymethane

Topics

• Adenoma (chemically induced, etiology, metabolism)
• Animals
• Azoxymethane (toxicity)
• Cell Transformation, Neoplastic (metabolism)
• Colitis (chemically induced, complications)
• Colonic Neoplasms (chemically induced, etiology, metabolism)
• Cytokines (metabolism)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Disease Susceptibility
• Epithelial Cells (metabolism)
• Female
• Inflammation
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B p50 Subunit (metabolism)
• NF-kappa B p52 Subunit (metabolism)
• Proto-Oncogene Proteins c-rel (metabolism)
• Signal Transduction