[show abstract][hide abstract] 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 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.
Proceedings of the National Academy of Sciences 08/2012; 109(35):14007-14012. · 9.74 Impact Factor