Abstract
Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in idiopathic pulmonary fibrosis (IPF) regulation is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 is yet to be investigated. Additionally, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual-luciferase reporter assay system were used to identify the target gene of miR-30a, and cell transfection was utilized to confirm this relationship. Ten–eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and miR-30a mimic and inhibitor transfection significantly reduced and increased the TET1 protein expression, respectively. Further experimentation verified that the TET1 siRNA interference could inhibit Drp-1 promoter hydroxymethylation. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit TET1 expression through base pairing with complementary sites in the 3′untranslated region to regulate Drp-1 promoter hydroxymethylation. Furthermore, miR-30a could act as a potential therapeutic target for IPF.
Highlights
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal fibrotic lung disease [1]
Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein1 (Drp-1) [12]
We further evaluated the circulating miR-30a expression in IPF patients and explored the miR-30a target gene of methylcytosine dioxygenase ten–eleven translocation 1 (TET1) and the regulatory mode between Ten–eleven translocation 1 (TET1) and Drp-1
Summary
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal fibrotic lung disease [1]. The mechanisms regarding the control of IPF progression by circulating miRNAs remain poorly understood. Our study focused on miR-30a regulation on the epithelial cell apoptosis during H2O2-induced IPF. The regulatory mechanism of miR-30 in IPF has never been systematically explored until now. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein (Drp-1) [12]. MiR-30a expression in IPF patients has not been evaluated. We further evaluated the circulating miR-30a expression in IPF patients and explored the miR-30a target gene of methylcytosine dioxygenase ten–eleven translocation 1 (TET1) and the regulatory mode between TET1 and Drp-1. We designed and applied the miR-30a agomir to identify and validate the therapeutic effect of miR-30a in vivo
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