RhoA-Dependent HGF and c-Met Mediate Gas6-Induced Inhibition of Epithelial-Mesenchymal Transition, Migration, and Invasion of Lung Alveolar Epithelial Cells.

Jung Jung,Kang Kang,Kim Kim,Choi Choi,Lee Lee,Yang Yang

doi:10.3390/biom9100565

Abstract

Previously, we demonstrated that growth arrest-specific protein 6 (Gas6)/Axl or Mer signaling inhibited the transforming growth factor (TGF)-β1-induced epithelial–mesenchymal transition (EMT) in lung epithelial cells. Hepatocyte growth factor (HGF) has also been shown to inhibit TGF-β1-induced changes in EMT markers. Here, we examined whether Gas6 signaling can induce the production of HGF and c-Met in lung alveolar epithelial cells to mediate the inhibition of EMT and to inhibit the migration and invasion of epithelial cells. The inhibition of the RhoA/Rho kinase pathway, using either a RhoA-targeted small interfering RNA (siRNA) or the Rho kinase pharmacologic inhibitor Y27362, prevented the inhibition of TGF-β1-induced EMT in LA-4 cells and primary alveolar type II (AT II) epithelial cells. The c-Met antagonist PHA-665752 also blocked the anti-EMT effects associated with Gas6. Moreover, treatment with Y27362 or PHA-665752 prevented the Gas6-mediated inhibition of TGF-β1-induced migration and invasion. Our data provided evidence that the RhoA-dependent production of HGF and c-Met mediated the Gas6-induced inhibition of EMT, migration and invasion in lung alveolar epithelial cells. Thus, Gas6/Axl and Mer/RhoA signaling may be necessary for the maintenance of homeostasis in the alveolar epithelium, via HGF and c-Met.

Highlights

Pulmonary fibrosis is a potentially fatal disease that is characterized by continuous alveolar epithelial injury and dysregulated repair, leading to myofibroblast accumulation and the excessive deposition of extracellular matrix (ECM) components and connective tissues
Here we examined the role of the Hepatocyte growth factor (HGF)-signaling pathway during the inhibitory effects of growth arrest-specific protein 6 (Gas6) on the epithelial–mesenchymal transition (EMT) process, as well as during the inhibitory effects of Gas6 on the migration and invasion of LA-4 and primary mouse alveolar type II (AT II) epithelial cells
We first examined whether Gas6 induces RhoA-dependent HGF secretion in LA-4 lung epithelial-like cells

Summary

Introduction

Pulmonary fibrosis is a potentially fatal disease that is characterized by continuous alveolar epithelial injury and dysregulated repair, leading to myofibroblast accumulation and the excessive deposition of extracellular matrix (ECM) components and connective tissues. Previous studies have indicated that efficient alveolar epithelial cell repair is critical for normal healing without fibrosis [1,2]. Local tissue myofibroblasts were thought to be the primary source of ECM components following injury [3]. ECM components are thought to derive from multiple sources [4], such as resident lung fibroblasts, bone marrow-derived fibrocytes, and other circulating fibroblast progenitor cells and the epithelial–mesenchymal transition (EMT) [4,5,6,7]. Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease but has the worst prognosis, with a median. Emerging evidence suggests that the EMT process is a major event during IPF pathogenesis [9,10,11]

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