| First Author | Stathopoulos GT | Year | 2007 |
| Journal | Proc Natl Acad Sci U S A | Volume | 104 |
| Issue | 47 | Pages | 18514-9 |
| PubMed ID | 18000061 | Mgi Jnum | J:127598 |
| Mgi Id | MGI:3763971 | Doi | 10.1073/pnas.0705316104 |
| Citation | Stathopoulos GT, et al. (2007) Epithelial NF-{kappa}B activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci U S A 104(47):18514-9 |
| abstractText | 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. |
