MiR-503 modulates epithelial-mesenchymal transition in silica-induced pulmonary fibrosis by targeting PI3K p85 and is sponged by lncRNA MALAT1

Abstract

Silicosis is a kind of chronic, progressive and incurable lung fibrotic diseases with largely unknown and complex pathogenesis and molecular mechanisms. Mounting evidence suggests that microRNAs (miRNAs, miRs) are involved in the pathogenesis of silicosis. Our previous study based on miRNA microarray had shown that the expression levels of miR-503 were down-regulated in mouse lung tissues of silica-induced pulmonary fibrosis. Here, we validated the decreased expression of miR-503 in the fibrotic mouse lung tissues, human bronchial epithelial cells (HBE) and human lung adenocarcinoma A549 cells which were exposed to silica. In addition, overexpressed miR-503 inhibited silica-induced pulmonary fibrosis by attenuating the severity and the distribution of lesions in vivo and limiting the process of epithelial-mesenchymal transition (EMT) in vitro. Our molecular study further demonstrated that PI3K p85 is one of the target genes of miR-503 and the downstream molecules (Akt, mTOR and Snail) are tightly associated with EMT. Furthermore, the up-regulated lncRNA Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), acted as a competing endogenous RNA (ceRNA), can directly bound to miR-503, which indicated that lncRNA MALAT1 may modulate the expression of miR-503 thus triggering the activation of downstream fibrotic signaling pathways. Taken together, our data suggested that MALAT1-miR-503-PI3K/Akt/mTOR/Snail pathway plays critical roles in silica-induced pulmonary fibrosis.Silicosis, a kind of interstitial lung fibrotic disease, is incurable and irreversible, and usually caused by occupational exposure to silica dust 1, 2 . Alveolar epithelial cell injury and hyperplasia, persistent inflammation, extracellular matrix deposition and subsequent aberrant wound healing are common characteristics of silicosis 3 . In the process of pulmonary fibrosis, epithelial cells and macrophages are stimulated by the silica particles, secreting large amount of cytokines and inflammatory mediators, thus promoting epithelial cells transform to myofibroblasts through epithelial metaplasia, apoptosis, fibrocyte recruitment and EMT 4 . However, the molecular mechanisms underlying pulmonary fibrosis are still unclear.Epithelial-mesenchymal transition (EMT) means a process that polar adjacent epithelial cells transform to non-polar mesenchymal cells which lack cell-cell contacts and increase cell mobility 5 . EMT plays an important role in the development of pulmonary fibrosis and has been proved to be a valuable incident which occurs in the alveolar type II epithelial cells 6 . Myofibroblasts accumulate and secrete large amount of collagen during the formation of fibrosis, which lead to the failure of lung function. Studies have shown that pulmonary fibrosis is a process undergoing the activation of interstitial fibroblasts that convert to myofibroblasts to form the fibrotic collagen network 7 . Moreover, a population of the fibroblasts involved in the fibrotic process is thought to originate from the transition of the epithelial cel...

lncRNA PFAL promotes lung fibrosis through CTGF by competitively binding miR‐18a

“…Chen et al (32) found that up-regulation of lncRNA in colorectal cancer liver metastasis (UICLM) promoted colorectal cancer metastasis by acting as a ceRNA of miR-215. Yan et al (33) reported that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promoted EMT by binding to miR503, which then resulted in lung fibrosis. A recent study by Liu et al (34) demonstrated that lncRNA PCF contributed to lung fibrosis through promotion of activated epithelial cell proliferation by binding to miR-344a-5p.…”

The role of lncRNA MALAT1 in cardiovascular disease

“…22 MALAT1 inhibited infiltration of inflammatory CD45+ cells partly via sponging miR-503. 41 The exosomes containing MALAT1 released from Ox-LDL-treated ECs could promote the M2 macrophage and IL-10 production and inhibit the M1 macrophage and IL-12 production. 51 High glucose also induces inflammatory cytokine such as IL-6 and tumor necrosis factor α (TNF-α) through MALAT1 mediated upregulation of serum amyloid antigen 3 (SAA3) in HUVECs.…”

“…MALAT1 could reverse the ox‐LDL induced inflammation by sponging miR‐155, thereby increasing the level of SOCS1 . MALAT1 inhibited infiltration of inflammatory CD45+ cells partly via sponging miR‐503 . The exosomes containing MALAT1 released from Ox‐LDL‐treated ECs could promote the M2 macrophage and IL‐10 production and inhibit the M1 macrophage and IL‐12 production .…”

“…35,40 Knockdown of MALAT1 caused increased plaque size and infiltration of inflammatory CD45 + cells partly via regulation of miR-503. 41 Furthermore, MALAT1 were also involved in regulation of endothelial dysfunction, lipid accumulation and chronic inflammation, which contributed to development of atherosclerosis. 40,42,43…”

The Role of miRNAs in Idiopathic Pulmonary Fibrosis

“…However, little is known about miRNA functions in IPF; much of the functional data has been inferred from chemically induced mouse IPF models. In the lungs of mouse IPF models, miR-21, miR-9, and miR-155 were increased [19,21,30], and miR-26, miR-101, miR-139, miR-200, miR-326, miR-489, miR-503, and miR-708 were decreased [24,[31][32][33][34][35][36][37]. Furthermore, miR-21 expression was increased in myofibroblasts from IPF lungs, and its inhibition in mouse IPF models attenuated the disease severity [19].…”