Recent studies suggest the importance of the transition of airway epithelial cells (EMT) in
pulmonary fibrosis, and also indicate a role for Wingless
protein (Wnt)/β-
catenin signaling in
idiopathic pulmonary fibrosis. We investigated the possible role of the Wnt signaling pathway in inducing EMT in lung epithelial cells, and sought to unravel the role of c-Jun-N-terminal-kinase-1 (JNK1). The exposure of C10 lung epithelial cells or primary mouse tracheal epithelial cells (MTECs) to Wnt3a resulted in increases in JNK phosphorylation and nuclear β-
catenin content. Because the role of β-
catenin as a transcriptional coactivator is well established, we investigated
T-cell factor/lymphocyte-enhancement factor (TCF/LEF) transcriptional activity in C10 lung epithelial cells after the activation of Wnt. TCF/LEF transcriptional activity was enhanced after the activation of Wnt, and this increase in TCF/LEF transcriptional activity was diminished after the small interfering (si)
RNA-mediated ablation of JNK. The activation of the Wnt pathway by Wnt3a, or the expression of either wild-type or constitutively active β-
catenin (S37A), led to the activation of an EMT transcriptome, manifested by the increased
mRNA expression of CArG box-binding
factor-A, fibroblast-specific
protein (FSP)-1, α-smooth muscle actin (α-SMA), and
vimentin, increases in the content of α-SMA and FSP1, and the concomitant loss of
zona occludens-1. The
siRNA-mediated ablation of β-
catenin substantially decreased Wnt3a-induced EMT. The
siRNA ablation of JNK1 largely abolished Wnt3a, β-
catenin, and β-
catenin S37a-induced EMT. In MTECs lacking Jnk1, Wnt3a-induced increases in nuclear β-
catenin, EMT transcriptome, and the content of α-SMA or FSP1 were substantially diminished. These data show that the activation of the Wnt signaling pathway is capable of inducing an EMT program in lung epithelial cells through β-
catenin, and that this process is controlled by JNK1.