Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis.
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.
Stathopoulos
Georgios T
GT
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. gstathop@med.uoa.gr
Sherrill
Taylor P
TP
Cheng
Dong-Sheng
DS
Scoggins
Robert M
RM
Han
Wei
W
Polosukhin
Vasiliy V
VV
Connelly
Linda
L
Yull
Fiona E
FE
Fingleton
Barbara
B
Blackwell
Timothy S
TS
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*
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014520:Urethane