MicroRNA-708-3p as a potential therapeutic target via the ADAM17-GATA/STAT3 axis in idiopathic pulmonary fibrosis

Bo Liu,Xiaodong Song,Jinjin Zhang,Rongrong Li,Chao Meng,Changjun Lv,Jie Zhang

doi:10.1038/emm.2017.311

Abstract

MicroRNAs (miRNAs) are important diagnostic markers and therapeutic targets for many diseases. However, the miRNAs that control the pathogenesis of idiopathic pulmonary fibrosis (IPF) and act as potential therapeutic targets for the disease are rarely studied. In the present study, we analyzed the function and regulatory mechanism of microRNA-708-3p (miR-708-3p) and evaluated this marker’s potential as a therapeutic target in IPF. The clinical and biological relevance of fibrogenesis for miR-708-3p was assessed in vivo and in vitro, specifically in matching plasma and tissue samples from 78 patients with IPF. The data showed that the miR-708-3p levels decreased during fibrosis and inversely correlated with IPF. The experiments showed that the decreased miR-708 promoter activity and primer-miR-708(pri-miR-708) expression were the potential causes. By computational analysis, a dual luciferase reporter system, rescue experiments and a Cignal Finder 45-Pathway system with siADAM17 and a miR-708-3p mimic, we identified that miR-708-3p directly regulates its target gene, a disintegrin and metalloproteinase 17 (ADAM17), through a binding site in the 3′ untranslated region, which depends on the GATA/STAT3 signaling pathway. Finally, an miR-708-3p agomir was designed and used to test the therapeutic effects of the miR-708-3p in an animal model. Small-animal imaging technology and other experiments showed that the dynamic image distribution of the miR-708-3p agomir was mainly concentrated in the lungs and could block fibrogenesis. In conclusion, the miR-708-3p–ADAM17 axis aggravates IPF, and miR-708-3p can serve as a potential therapeutic target for IPF.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia in adults.[1]
A dual luciferase reporter system, rescue experiments and a Cignal Finder 45-Pathway system with siADAM17 and a miR-708-3p mimic, we identified that miR-708-3p directly regulates its target gene, a disintegrin and metalloproteinase 17 (ADAM17), through a binding site in the 3′ untranslated region, which depends on the GATA/STAT3 signaling pathway
The Pearson correlation coefficient clarified that miR-708-3p inversely correlated with α-Smooth muscle actin (α-SMA) (Figure 1c) and suggested that miR-708-3p expression may be inversely correlated with fibrosis

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia in adults.[1]. MiRNA is critical in the development and dysregulation that leads to diseases, as well as being an important diagnostic marker and therapeutic target.[4,5]. All of the examined tumor types were characterized by globally abnormal miRNA expression patterns, and miRNA expression profiles provided significant information on tumor classification, prognosis and therapeutic response.[10,11,12] IPF exhibits several cancer-like pathogenic features and is a neoproliferative lung disorder. Fundamental pathogenic hallmarks for both IPF and cancer include epigenetic and genetic abnormalities and functional features, such as uncontrolled proliferation, resistance to apoptosis and high migration rates.[13,14,15] unlike other studies on miRNAs in cancers, studies have not revealed the precise miRNA regulation and mechanism controlling IPF pathogenesis

Methods

Results

Conclusion