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

Helena Shaked, Lorne J. Hofseth, Alena Chumanevich, Alexander A. Chumanevich, Jin Wang, Yinsheng Wang, Koji Taniguchi, Monica Guma, Steve Shenouda, Hans Clevers, Curtis C. Harris, Michael Karin

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90 Citations (Scopus)

Abstract

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 damagemarkers 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.

Original languageEnglish
Pages (from-to)14007-14012
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number35
DOIs
Publication statusPublished - 28 Aug 2012

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    Shaked, H., Hofseth, L. J., Chumanevich, A., Chumanevich, A. A., Wang, J., Wang, Y., Taniguchi, K., Guma, M., Shenouda, S., Clevers, H., Harris, C. C., & Karin, M. (2012). Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation. Proceedings of the National Academy of Sciences of the United States of America, 109(35), 14007-14012. https://doi.org/10.1073/pnas.1211509109