Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.
Proc Natl Acad Sci U S A
; 109(35): 14007-12, 2012 Aug 28.
Article
em En
| MEDLINE
| ID: mdl-22893683
ABSTRACT
The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkß(EE)(IEC) transgenic mice expressing constitutively active IκB kinase ß (IKKß) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkß(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, Ikkß(EE)(IEC) mice exhibited more ß-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkß(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 Ikkß(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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NF-kappa B
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Proteína da Polipose Adenomatosa do Colo
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Óxido Nítrico Sintase Tipo II
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Quinase I-kappa B
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos