Cigarette smoking induces lung cancer tumorigenesis via upregulation of the WNT/β-catenin signaling pathway

Abstract

Lung cancer has the highest mortality rate compared to any other cancer worldwide, and cigarette smoking is one of the major etiological factors. How cigarette smoke (CS) induces tumorigenesis in healthy cells is still not completely understood. In this study, we treated healthy human bronchial epithelial cells (16HBE14o) with 1 % cigarette smoke extract (CSE) for one week. The CSE exposed cells showed upregulation of WNT/β-catenin pathway genes like WNT3, DLV3, AXIN and β-catenin, 30 oncology proteins were found to be upregulated after CSE treatment. Further, we explored whether the role of extracellular vesicles (EVs) obtained from CSE exposed cells can induce tumorigenesis. We observed that CSE EVs induced migration of healthy 16HBE14o cells by upregulation of various oncology proteins in recipient cells like AXL, EGFR, DKK1, ENG, FGF2, ICAM1, HMOX1, HIF1a, SERPINE1, SNAIL, HGFR, PLAU which are related to WNT signaling, epithelial mesenchymal transition (EMT) and Inflammation, whereas inflammatory marker, GAL-3 and EMT marker, VIM were downregulated. Moreover, β-catenin RNA was found in CSE EVs, upon treatment of these EVs to healthy cells, the β-catenin gene level was decreased in recipient cells compared to healthy 16HBE14o cells, indicating the utilisation of β-catenin RNA in healthy cells. Overall, our study suggests that CS treatment can induce tumorigenesis of healthy cells by upregulating WNT/β-catenin signaling in vitro and human lung cancer patients. Therefore targeting the WNT/β-catenin signaling pathway is involved in tumorigenesis inhibition of this pathway could be a potential therapeutic approach for cigarette smoke induced lung cancer.