Regulatory Mechanism Of MiR-708-3p In Idiopathic Pulmonary Fibrosis By Targeting ADAM17

Objective:Idiopathic pulmonary fibrosis(IPF)is defined as a specific form of chronic,progressive fibrosing interstitial pneumonia of unknown cause,occurring primarily in older adults,and limited to the lungs.Surgical removal is the only cure for idiopathic pulmonary fibrosis(IPF).Therefore,early IPF detection is important.MicroRNAs(miRNAs)are important diagnostic markers and therapeutic targets for many diseases.However,studies did not focus on miRNA mechanisms that control IPF pathogenesis and IPF diagnostic markers and therapeutic targets.We report regulatory mechanism of miR-708-3p,which can act as potential therapeutic target for IPF.Methods:We analyzed matching plasma and tissue samples from 78 IPF patients.We evaluated miR-708-3p expression and function in vivo and in vitro.Target gene of miR-708-3p was identified using computational analysis and Dual-luciferase Reporter Assay System.Rescue experiments were used to confirm this relationship.In IPF-associated aberrant signaling pathways,miR-708-3p regulation was examined by Cignal Finder 45-Pathway and confirmed by gene interference.Finally,miR-708-3p agomir was designed and used to identify and validate therapeutic effects of miR-708-3p in vivo.Results:Expression of miR-708-3p decreased in IPF.Disintegrin and metalloproteinase 17(ADAM 17)were validated as direct targets of miR-708-3p.miR-708-3p directly regulates ADAM 17 through binding site in 3’untranslated region,which can mediate GATA/STAT3-dependent signaling pathway.Aberrant activation of miR-708-3p axis contributes to expressional changes inepithelial cadherin(E-cadherin),α-SMA,vimentin,Snail,and collagens Ⅰ and Ⅲ,thereby resulting in fibrogenesis in patients.miR-708-3p has clinical and biological relevance of IPF because it is linked to elevation of E-cadherin and reduction of a-SMA,vimentin,Snail,collagens I and III,key mediators of fibrosis.Conclusions:Mechanism of miR-708-3p-ADAM17 axis fosters progression of IPF deterioration.IPF susceptibility is reflected by plasma miR-708-3p level and its association with AD AM17.Targeting miR-708-3p can be evaluated as potential therapeutic IPF approach.