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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-08, Vol.109 (35), p.14007-14012
• Main Authors: Shaked, Helena, Hofseth, Lorne J, Chumanevich, Alena, Chumanevich, Alexander A, Wang, Jin, Wang, Yinsheng, Taniguchi, Koji, Guma, Monica, Shenouda, Steve, Clevers, Hans, Harris, Curtis C, Karin, Michael
• Format: Article
• Language: English
• Subjects: Adenomatous Polyposis Coli Protein - metabolism; Animals; beta Catenin - metabolism; Biological Sciences; Cancer; Colitis - metabolism; Colitis - pathology; Colorectal cancer; colorectal neoplasms; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA; DNA damage; DNA Damage - physiology; Epithelial cells; Epithelial Cells - metabolism; Female; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; inducible nitric oxide synthase; Inflammation; intestinal mucosa; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Lesions; loci; Loss of Heterozygosity - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B - metabolism; Nitric Oxide Synthase Type II - metabolism; Oxides; Reactive Nitrogen Species - metabolism; Stem cells; Stem Cells - cytology; transcription factor NF-kappa B; transgenic animals; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1211509109

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.