Gas6 Prevents Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells via Production of PGE2, PGD2 and Their Receptors

Abstract

The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-β1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-β1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors.

Celastrol mitigates high glucose‐induced inflammation and apoptosis in rat H9c2 cardiomyocytes via miR‐345‐5p/growth arrest‐specific 6

“…13 Gas6 interaction with TAM modulates downstream signaling, involving various biological processes, including cell growth, migration, apoptosis, inflammation and epithelial-mesenchymal transition. 14,15 Gas6 can abrogate serum starvation-induced endothelial cell apoptosis via phosphorylation of the serine-threonine kinase Akt. 16 Moreover, Gas6 exhibits an attenuation of inflammation in multiple cell or animal disease models.…”

Novel AXL-specific inhibitor ameliorates kidney dysfunction through the inhibition of epithelial-to-mesenchymal transition of renal tubular cells

“…The up-regulation of AXL causes the phosphorylation of Smad3, which is regulated by TGFβ signaling and is well correlated with an increase in the metastasis of cancer [43][44][45][46]. However it remains controversial whether AXL signaling is a positive regulator of EMT [47]. In this study we have shown that AXL activation is indispensable for TGFβ1 to promote EMT in NRK-52E renal tubular epithelial cells (Fig 7A-7C).…”

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

“…Next, we examined the contributions made by Axl and Mer signaling to Gas6-induced RhoA activity and HGF expression in LA-4 cells, using two kinds of Axl or Mer -specific siRNAs. LA-4 cells were transfected with either an Axl - or Mer -specific siRNA or a negative control siRNA and cultured for 48 h. With Axl or Mer protein knockdown (Figure S2A,B) [31], Gas6-induced RhoA activity in LA-4 cells was substantially suppressed (Figure 2A; Figure S2C). Concomitantly, the Gas6-induced increase in HGF expression levels was prevented by the silencing of either Axl or Mer RNA, at both the gene and protein levels (Figure 2B,C; Figure S2D,E).…”

“…However, the upregulation of HGF promotes carcinogenesis and EMT in hepatocellular carcinomas via AKT and cyclooxygenase-2 (COX-2) pathways [29,30]. Recently, we reported that Gas6 inhibits TGF-β1-induced EMT and signaling in lung epithelial cells, via the activation of Axl or Mer and the COX-2-dependent production of prostaglandin E 2 (PGE 2 ) and prostaglandin D 2 (PGD 2 ) [31]. Based on these findings, here we examined the role of the HGF-signaling pathway during the inhibitory effects of Gas6 on the 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.…”