Cigarette smoke enhances initiation and progression of lung cancer by mutating Notch1/2 and dysregulating downstream signaling molecules

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 nonsmokers 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.