Lung cancer is the principal cause of cancer mortality in the world, and its frequency is increasing. Hence, improved therapeutic options are imperative. There is a strong correlation between tobacco exposure and lung carcinogenesis, and the best protection against lung cancer is the avoidance of smoking. Advances in lung cancer therapy require a greater understanding of the molecular pathogenesis of this disease. Previously, we showed that the leucine zipper family transcription factor CCAAT/enhancer binding protein alpha (C/EBPα), a proposed tumor suppressor in acute myeloid leukemia (AML), is down-regulated in non-small cell lung cancer. Furthermore, ectopic expression of C/EBPα in the lung cancer cell lines led to significant growth reduction attributable to proliferation arrest, morphological changes characteristic of differentiation, and apoptosis. Additionally, mice with specific conditional loss of C/EBPα in the lung showed symptoms of respiratory distress accompanied by perinatal death, therefore hinting to potential therapeutical benefits that might be obtained by exploring the C/EBPα pathway in patients with respiratory distress syndrome. Based on these observations, we are exploring the effects of C/EBPα down-regulation in experimental models of lung cancer and tobacco-damaged epithelium, using our inducible models of lung-specific C/EBPα deletion. We are also analyzing the differentiation and self-renewal capabilities of C/EBPα-deleted pulmonary stem cells, in order to gain knowledge on the molecular mechanisms that C/EBPα is orchestrating in lung stem cells.
Characterization of critical regulatory mechanisms governed by the master regulator C/EBPα as well as the aberrant differentiation pathways in C/EBPα-deleted pulmonary stem cells would be of critical relevance for our better understanding the pathogenesis of as well as the identification of novel treatment targets for tobacco-related lung diseases, such as lung cancer and emphysema.