Nicotine-induced epithelial-mesenchymal transition via Wnt/β-catenin signaling in human airway epithelial cells

Zou W, Zou Y, Zhao Z, Li B, Ran P. Nicotine-induced epithelial-mesenchymal transition via Wnt/beta-catenin signaling in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 304: L199-L209, 2013. First published November 30, 2012; doi: 10.1152/ajplung.00094.2012.-Epithelial-mesenchymal transition (EMT) has been proposed to be a mechanism in airway remodeling, which is a characteristic of chronic obstructive pulmonary disease (COPD). Studies have shown that cigarette smoke and nicotine are factors that induce Wnt/beta-catenin activation, which is a pathway that has also been implicated in EMT. The main aim of this study was to test whether human bronchial epithelial cells are able to undergo EMT in vitro following nicotine stimulation via the Wnt3a/beta-catenin signaling pathway. We show that nicotine activates the Wnt3a signal pathway, which leads to the translocation of beta-catenin into the nucleus and activation of beta-catenin/Tcf-dependent transcription in the human bronchial epithelial cell (HBEC) line. This accumulation was accompanied by an increase in smooth muscle actin, vimentin, matrix metalloproteinases-9, and type I collagen expression as well as downregulation of E-cadherin, which are typical characteristics of EMT. We also noted that the release of TGF-beta(1) from these cells was stimulated by nicotine. Knockdown of Wnt3a with small interfering RNA (siRNA) prevented these effects, implying that beta-catenin activation in these responses is Wnt3a dependent. Furthermore, specific knockdown of TGF-beta(1) with TGF-beta(1) siRNA partially prevented nicotine-induced EMT, suggesting that TGF-beta(1) has a role in nicotine-mediated EMT in HBECs. These results suggest that HBECs are able to undergo EMT in vitro upon nicotine stimulation via the Wnt3a/beta-catenin signaling pathway.