Abstract
Lung cancer is the primary cause of cancer related deaths in the western world and smoking significantly increases the risk of developing lung cancer. Smoking enhances lung cancer initiation and progression. The effects of cigarette smoke on lung cancer are mediated by the presence of highly mutagenic substances, including nicotine, leading to mutations in oncogenes and tumor suppressor genes. An emerging pathway in cancer is the Notch signaling pathway which is essential for embryonic lung development and tissue homeostasis. The role of Notch signaling in lung cancer remains controversial and no studies have directly linked cigarette exposure to mutations in Notch. Therefore, we investigated the direct effect of Notch signaling pathways on cigarette-induced lung tumors and the correlation between smoking and mutations in Notch leading to altered downstream signaling. Human cell lines, mouse models and clinical lung cancer samples were utilized in this study. Cigarette-induced in vitro human lung cancer models and in vivo mouse models demonstrated strong effects of cigarette exposure on the Notch signaling pathway. Immunohistochemistry (IHC) of 50 clinical samples collected from smokers and non-smokers with and without lung cancer also demonstrated a link between smoking and changes in Notch signaling. Finally, 34 lung cancer samples analyzed through direct sequencing indicated smoking significantly increased small nucleotide polymorphisms (SNPs) in Notch 1 and 2 and specific SNPs significantly modulated expression levels of downstream signaling pathway molecules. Taken together, these results demonstrate a direct effect of smoking on the Notch signaling pathway leading to lung cancer initiation and progression.
Highlights
The principal cause of cancer related deaths in the western world is lung cancer
The correlative links between smoking and lung www.impactjournals.com/oncotarget cancer were known since the 1930s it was not until the 1980s that scientist determined that carcinogens in tobacco smoke induced mutations in specific oncogenes and tumor suppressor genes leading to the initiation and progression of lung cancer [2]
This was achieved by culturing human bronchial epithelial cells (BEP2D) in serum free LHC-8 medium supplemented with cigarette smoke condensate (CSC) at a concentration of 1 cigarette/ml for an extended period of time
Summary
The principal cause of cancer related deaths in the western world is lung cancer. Smoking significantly increases the risk of developing numerous tumor types, but none more so than lung cancers. 34 lung cancer samples analyzed through direct sequencing indicated smoking significantly increased small nucleotide polymorphisms (SNPs) in Notch 1 and 2 and specific SNPs significantly modulated expression levels of downstream signaling pathway molecules. These results indicate that CSC treated BEP2D cells provides an excellent in vitro model to study cigaretteinduced lung cancer initaiton and progression.
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