Targeting the DNM3OS / miR-199a~214 cluster for the treatment of fibroproliferative diseases

Abstract

One Sentence Summary: The DNM3OS lncRNA is a reservoir of fibromiRs with major functions in fibroblast response to TGF-β and represents a valuable therapeutic target for refractory fibrotic diseases such as idiopathic pulmonary fibrosis (IPF).not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/242040 doi: bioRxiv preprint first posted online Jan. 4, 2018; AbstractGiven the paucity of effective treatments for fibrotic disorders, new insights into the deleterious mechanisms controlling fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Here, we identified the long non-coding RNA DNM3OS as a critical downstream effector of TGF-β-induced myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to 3 distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way, through two modes of action consisting of either signal amplification or mediation. Finally, we provide preclinical evidence that interfering with DNM3OS function using distinct strategies not only prevents lung and kidney fibrosis but also improves established lung fibrosis, providing thus a novel paradigm for the treatment of refractory fibrotic diseases such as idiopathic pulmonary fibrosis.not peer-reviewed)

Molecular Signatures of Idiopathic Pulmonary Fibrosis

“…Genomic miRNA profiles have revealed several miRNAs that are known to affect fibroproliferation, epithelial-mesenchymal transition (EMT), and the TGF-β1 signaling pathway (28)(29)(30)(31)(32). Although studies of long noncoding RNAs in pulmonary fibrosis are limited, there appears to be an anti-fibrotic role for FENDRR (33) and a pro-fibrotic role for DNM3OS (34). In addition, studies in peripheral blood have identified biomarkers of disease (35) and disease outcome (36,37).…”

HOXA5-induced lncRNA DNM3OS promotes human embryo lung fibroblast fibrosis via recruiting EZH2 to epigenetically suppress TSC2 expression

“…LncRNA Airn alleviate liver fibrosis via the Kruppel-like factor 2 (KLF2)-endothelial nitric oxide synthase (eNOS)-soluble guanylate cyclase (sGC) pathway ( 18 ), while Zinc finger E-box binding homeobox 1 antisense 1 ( ZEB1-AS1 ) contributes to lung fibrosis by facilitating EMT ( 19 ). LncRNA DNM3OS is induced by TGF-β1 which results in the production of profibrotic microRNAs (miRNAs) ( 20 ), and targeting DNM3OS shows promising therapeutic effects in fibroproliferative diseases including IPF ( 21 ). As a critical regulator for IPF, the underlying molecular mechanism of DNM3OS in IPF pathogenesis remains elusive.…”