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Chronic epithelial NF-?B activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.


ABSTRACT: The role of NF-?B activation in tumor initiation has not been thoroughly investigated. We generated Ikk?(EE)(IEC) transgenic mice expressing constitutively active I?B kinase ? (IKK?) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikk?(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, Ikk?(EE)(IEC) mice exhibited more ?-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/?IEC) mice, and their survival was severely compromised. IEC of Ikk?(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 Ikk?(EE)(IEC)/Apc(+/?IEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early ?-catenin(+) lesions and tumor load. The results suggest that persistent NF-?B activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.

SUBMITTER: Shaked H 

PROVIDER: S-EPMC3435160 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation.

Shaked Helena H   Hofseth Lorne J LJ   Chumanevich Alena A   Chumanevich Alexander A AA   Wang Jin J   Wang Yinsheng Y   Taniguchi Koji K   Guma Monica M   Shenouda Steve S   Clevers Hans H   Harris Curtis C CC   Karin Michael M  

Proceedings of the National Academy of Sciences of the United States of America 20120814 35


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 exhibite  ...[more]

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