Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.
The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE)(IEC) transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkβ(EE)(IEC) mice exhibited more β-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkβ(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin(+) lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.
Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Helena
H
Shaked
Lorne J
LJ
Hofseth
Alena
A
Chumanevich
Alexander A
AA
Chumanevich
Jin
J
Wang
Yinsheng
Y
Wang
Koji
K
Taniguchi
Monica
M
Guma
Steve
S
Shenouda
Hans
H
Clevers
Curtis C
CC
Harris
Michael
M
Karin
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004249:DNA Damage / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D051176:beta Catenin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051550:I-kappa B Kinase