title: Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis.
abstract: Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NF-kappaB, a central effector of inflammatory responses, is frequently activated in non-small-cell lung cancer, but its role in tumor promotion has not been studied. Several lines of evidence indicate that ethyl carbamate (urethane)-induced lung tumor formation, a prototypical mouse model of multistage lung carcinogenesis, is potentiated by inflammation. We found that mouse strains susceptible to lung tumor formation (FVB, BALB/c) exhibited early NF-kappaB activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NF-kappaB or induce lung inflammation. In FVB mice, we identified urethane-induced NF-kappaB activation in airway epithelium, as well as type II alveolar epithelial cells and macrophages. Using an inducible transgenic mouse model (FVB strain) to express a dominant inhibitor of NF-kappaB specifically in airway epithelial cells, we found that urethane-induced lung inflammation was blocked and tumor formation was reduced by >50%. Selective NF-kappaB inhibition resulted in increased apoptosis of airway epithelial cells at 2 weeks after urethane treatment in association with a marked reduction of Bcl-2 expression. These studies indicate that NF-kappaB signaling in airway epithelium is integral to tumorigenesis in the urethane model and identify the NF-kappaB pathway as a potential target for chemoprevention of lung cancer.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. gstathop@med.uoa.gr
authors.forename: Georgios T
authors.initials: GT
authors.lastname: Stathopoulos
authors.forename: Taylor P
authors.initials: TP
authors.lastname: Sherrill
authors.forename: Dong-Sheng
authors.initials: DS
authors.lastname: Cheng
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scoggins
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Linda
authors.initials: L
authors.lastname: Connelly
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Yull
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014520:Urethane / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014520:Urethane