Long Noncoding RNA FENDRR Inhibits Lung Fibroblast Proliferation via a Reduction of β-Catenin

Lakmini Kumari Senavirathna,Dao Xu,Pulavendran Sivasami,Chaoqun Huang,Lin Liu,Quanjin Dang,Maria Cristina Munteanu,Xiaoyun Yang,Yurong Liang,Kishore Vaddadi,Paul Cheresh,David W Kamp,Gayan Bamunuarachchi,Sankha Hewawasam

doi:10.3390/ijms22168536

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and usually lethal lung disease and it has been widely accepted that fibroblast proliferation is one of the key characteristics of IPF. Long noncoding RNAs (lncRNAs) play vital roles in the pathogenesis of many diseases. In this study, we investigated the role of lncRNA FENDRR on fibroblast proliferation. Human lung fibroblasts stably overexpressing FENDRR showed a reduced cell proliferation compared to those expressing the control vector. On the other hand, FENDRR silencing increased fibroblast proliferation. FENDRR bound serine-arginine rich splicing factor 9 (SRSF9) and inhibited the phosphorylation of p70 ribosomal S6 kinase 1 (PS6K), a downstream protein of the mammalian target of rapamycin (mTOR) signaling. Silencing SRSF9 reduced fibroblast proliferation. FENDRR reduced β-catenin protein, but not mRNA levels. The reduction of β-catenin protein levels in lung fibroblasts by gene silencing or chemical inhibitor decreased fibroblast proliferation. Adenovirus-mediated FENDRR transfer to the lungs of mice reduced asbestos-induced fibrotic lesions and collagen deposition. RNA sequencing of lung tissues identified 7 cell proliferation-related genes that were up-regulated by asbestos but reversed by FENDRR. In conclusion, FENDRR inhibits fibroblast proliferation and functions as an anti-fibrotic lncRNA.

Highlights

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive scarring lung disease categorized under idiopathic interstitial pneumonia [1,2]
Based on our previous studies, we found that FENDRR binds with serine-arginine (SR) rich splicing factor 9 (SRSF9) [15] which is known to regulate mammalian target of rapamycin signaling [23]
We showed that FENDRR, bound with serine-arginine rich splicing factor 9 (SRSF9), inhibited the mammalian target of rapamycin (mTOR) signaling pathway, and reducing β-catenin protein levels

Summary

Introduction

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive scarring lung disease categorized under idiopathic interstitial pneumonia [1,2]. Lung fibroblast proliferation is a main characteristic of IPF as it results in extracellular matrix deposition, followed by damaging the lung parenchyma. It is believed that repeated micro-injuries to lung epithelium lead to aberrant proliferation and activation of lung fibroblasts, the failure to properly regulate the repair process, and the development of fibrosis [3,4]. Several studies have shown that the involvement of lncRNAs in pulmonary fibrosis [10,11,12,13,14]. Our previous study has shown that FOXF1 Adjacent Non-Coding Developmental Regulatory

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Results

Conclusion