Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis
Epithelial NF-κB activation promotes urethane-induced lung carcinogenesis
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DOI：
10.1073/pnas.0705316104
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发表时间：
2007-11-20
影响因子：
11.1
通讯作者：
Blackwell, Timothy S.
中科院分区：
文献类型：
--
作者：
Stathopoulos, Georgios T.;Sherrill, Taylor P.;Blackwell, Timothy S.
慢性炎症与几个器官系统的致癌作用有关。在肺中，NF-κ B B，一种炎症反应的中枢效应物，在非小细胞肺癌中经常被激活，但其在肿瘤促进中的作用尚未被研究。一些证据表明，氨基甲酸乙酯（氨基甲酸乙酯）诱导的肺肿瘤形成，一个典型的小鼠模型的多阶段肺癌，是加强炎症。我们发现，对肺肿瘤形成敏感的小鼠品系（FVB，BALB/c）在乌拉坦治疗后在肺中表现出早期NF-κ B活化和炎症。然而，耐药菌株（C57 B6）未能激活NF-κ B或诱导肺部炎症。在FVB小鼠中，我们鉴定了呼吸道上皮细胞以及II型肺泡上皮细胞和巨噬细胞中的IgE诱导的NF-κ B活化。使用诱导型转基因小鼠模型（FVB品系）在气道上皮细胞中特异性表达NF-κ B的显性抑制剂，我们发现，抑制剂诱导的肺部炎症被阻断，肿瘤形成减少> 50%。选择性NF-κ B抑制导致乌拉坦治疗后2周气道上皮细胞凋亡增加，与Bcl-2表达显著降低相关。这些研究表明，在尿烷模型中，气道上皮中的NF-κ B信号传导与肿瘤发生是不可或缺的，并将NF-κ B途径鉴定为肺癌化学预防的潜在靶点。
Chronic inflammation is linked to carcinogenesis in several organ systems. In the lungs, NF-kappa B, 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-kappa B activation and inflammation in the lungs after urethane treatment. However, a resistant strain (C57B6) failed to activate NF-kappa B or induce lung inflammation. In FVB mice, we identified urethane-induced NF-kappa B 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-kappa B specifically in airway epithelial cells, we found that urethane-induced lung inflammation was blocked and tumor formation was reduced by > 50%. Selective NF-kappa B 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-kappa B signaling in airway epithelium is integral to tumorigenesis in the urethane model and identify the NF-kappa B pathway as a potential target for chemoprevention of lung cancer.