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Long non-coding RNAs (lncRNAs) are important signal transduction regulators that act by various patterns. However, little is known about the molecular mechanisms of lncRNA related pathways in occupational lung fibrosis. Our previous study found that epithelial-mesenchymal transition (EMT) was one of the key events in silica-induced pulmonary fibrosis. This study showed that the lncRNA-ATB promoted EMT by acting as a miR-200c sponge. miR-200c was identified by miRNA array as a potential target of lncRNA-ATB and verified by dual luciferase reporter gene together with RNA pull-down assays. Moreover, our findings demonstrated that lncRNA-ATB is abundantly expressed during EMT of lung epithelial cells, which contributes to decreased levels of miR-200c. miR-200c targeted ZEB1 to relief silicosis by blocking EMT in vivo and in vitro. The results also suggested M2 macrophages secreted transforming growth factor-β1 (TGF-β1) to induce EMT process by activating lncRNA-ATB in epithelial cells. Collectively, silica-stimulated macrophages secreted TGF-β1 to induce lncRNA-ATB in epithelia cells, promoting EMT by binding with miR-200c and releasing ZEB1. These observations provide further understanding of the regulatory network of silica-induced pulmonary fibrosis and identify new therapeutic targets hopefully., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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 is one of the typical forms of pneumoconiosis characterized by abnormal proliferation of fibroblasts and deposition of extracellular matrix. Recent findings have shown that microRNAs and circular RNAs (circRNAs) are implicated in many diseases. However, the function of noncoding RNAs in pulmonary fibrosis remain to be elucidated. Here, miR-7 was found significantly decreased in silica-treated pulmonary epithelial cells as well as in fibrotic lung tissues of mice. Elevated expression of miR-7 via agomir injection relieved lung fibrosis in vivo. Further molecular study showed that miR-7 played its role against pulmonary fibrosis by blocking epithelial-mesenchymal transition (EMT) progression of human bronchial epithelial cells and A549 cells. Notably, transforming growth factor beta receptor 2 (TGFBR2) was identified as a target gene of miR-7 with bioinformatics tools, which was verified by dual luciferase receptor gene assay in human bronchial epithelial cells and A549 cells. Silica induced elevation of TGFBR2 could be abolished by exogenous expression of miR-7. Furthermore, bioinformatics software indicated that circRNA CDR1as had several binding sites for miR-7. The inhibitory effects of miR-7 on EMT and its target TGFBR2 were suppressed by circRNA CDR1as, which contributed to pulmonary fibrosis. Our studies also revealed overexpressed miR-7 could repress fibrogenesis of lung fibroblasts induced by TGF-β1. Collectively, circRNA CDR1as stimulated by silica could sponge miR-7 to release TGFBR2, plays an important role during pulmonary fibrosis by promoting EMT process. These results indicated that the interaction between miR-7 and circRNA CDR1as may exert important functions and provide potential therapeutic targets in lung fibrotic diseases. [ABSTRACT FROM AUTHOR]