TY - JOUR
T1 - Chronic epithelial NF-κB activation accelerates APC loss and intestinal tumor initiation through iNOS up-regulation
AU - Shaked, Helena
AU - Hofseth, Lorne J.
AU - Chumanevich, Alena
AU - Chumanevich, Alexander A.
AU - Wang, Jin
AU - Wang, Yinsheng
AU - Taniguchi, Koji
AU - Guma, Monica
AU - Shenouda, Steve
AU - Clevers, Hans
AU - Harris, Curtis C.
AU - Karin, Michael
PY - 2012/8/28
Y1 - 2012/8/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865534083&partnerID=8YFLogxK
U2 - 10.1073/pnas.1211509109
DO - 10.1073/pnas.1211509109
M3 - Article
C2 - 22893683
AN - SCOPUS:84865534083
SN - 0027-8424
VL - 109
SP - 14007
EP - 14012
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 35
ER -