miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II

Qian Zhang, Hong Ye, Fei Xiang, Lin Jie Song, Li Ling Zhou, Peng Cheng Cai, Jian Chu Zhang, Fan Yu, Huan Zhong Shi, Yunchao Su, Jian Bao Xin, Wan Li Ma

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3–5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.

Original languageEnglish (US)
Pages (from-to)728-738
Number of pages11
JournalMolecular Therapy
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Pulmonary Fibrosis
Bleomycin
Idiopathic Pulmonary Fibrosis
Epithelial-Mesenchymal Transition
Growth Factor Receptors
Transforming Growth Factors
MicroRNAs
Fibrosis
Down-Regulation
3' Untranslated Regions
Respiratory Insufficiency
Lung Diseases
Cell Movement
Up-Regulation
Animal Models
Messenger RNA

Keywords

  • TGF-β1
  • epithelial-mesenchymal transition
  • fibrosis
  • miR-18a
  • pleural mesothelial cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Zhang, Q., Ye, H., Xiang, F., Song, L. J., Zhou, L. L., Cai, P. C., ... Ma, W. L. (2017). miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II. Molecular Therapy, 25(3), 728-738. https://doi.org/10.1016/j.ymthe.2016.12.017

miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II. / Zhang, Qian; Ye, Hong; Xiang, Fei; Song, Lin Jie; Zhou, Li Ling; Cai, Peng Cheng; Zhang, Jian Chu; Yu, Fan; Shi, Huan Zhong; Su, Yunchao; Xin, Jian Bao; Ma, Wan Li.

In: Molecular Therapy, Vol. 25, No. 3, 01.03.2017, p. 728-738.

Research output: Contribution to journalArticle

Zhang, Q, Ye, H, Xiang, F, Song, LJ, Zhou, LL, Cai, PC, Zhang, JC, Yu, F, Shi, HZ, Su, Y, Xin, JB & Ma, WL 2017, 'miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II', Molecular Therapy, vol. 25, no. 3, pp. 728-738. https://doi.org/10.1016/j.ymthe.2016.12.017
Zhang, Qian ; Ye, Hong ; Xiang, Fei ; Song, Lin Jie ; Zhou, Li Ling ; Cai, Peng Cheng ; Zhang, Jian Chu ; Yu, Fan ; Shi, Huan Zhong ; Su, Yunchao ; Xin, Jian Bao ; Ma, Wan Li. / miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II. In: Molecular Therapy. 2017 ; Vol. 25, No. 3. pp. 728-738.
@article{2fcfc22ad07f4475a9ba9068b8d06b59,
title = "miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II",
abstract = "Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3–5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.",
keywords = "TGF-β1, epithelial-mesenchymal transition, fibrosis, miR-18a, pleural mesothelial cells",
author = "Qian Zhang and Hong Ye and Fei Xiang and Song, {Lin Jie} and Zhou, {Li Ling} and Cai, {Peng Cheng} and Zhang, {Jian Chu} and Fan Yu and Shi, {Huan Zhong} and Yunchao Su and Xin, {Jian Bao} and Ma, {Wan Li}",
year = "2017",
month = "3",
day = "1",
doi = "10.1016/j.ymthe.2016.12.017",
language = "English (US)",
volume = "25",
pages = "728--738",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - miR-18a-5p Inhibits Sub-pleural Pulmonary Fibrosis by Targeting TGF-β Receptor II

AU - Zhang, Qian

AU - Ye, Hong

AU - Xiang, Fei

AU - Song, Lin Jie

AU - Zhou, Li Ling

AU - Cai, Peng Cheng

AU - Zhang, Jian Chu

AU - Yu, Fan

AU - Shi, Huan Zhong

AU - Su, Yunchao

AU - Xin, Jian Bao

AU - Ma, Wan Li

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3–5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.

AB - Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease that typically leads to respiratory failure and death within 3–5 years of diagnosis. Sub-pleural pulmonary fibrosis is a pathological hallmark of IPF. Bleomycin treatment of mice is a an established pulmonary fibrosis model. We recently showed that bleomycin-induced epithelial-mesenchymal transition (EMT) contributes to pleural mesothelial cell (PMC) migration and sub-pleural pulmonary fibrosis. MicroRNA (miRNA) expression has recently been implicated in the pathogenesis of IPF. However, changes in miRNA expression in PMCs and sub-pleural fibrosis have not been reported. Using cultured PMCs and a pulmonary fibrosis animal model, we found that miR-18a-5p was reduced in PMCs treated with bleomycin and that downregulation of miR-18a-5p contributed to EMT of PMCs. Furthermore, we determined that miR-18a-5p binds to the 3′ UTR region of transforming growth factor β receptor II (TGF-βRII) mRNA, and this is associated with reduced TGF-βRII expression and suppression of TGF-β-Smad2/3 signaling. Overexpression of miR-18a-5p prevented bleomycin-induced EMT of PMC and inhibited bleomycin-induced sub-pleural fibrosis in mice. Taken together, our data indicate that downregulated miR-18a-5p mediates sub-pleural pulmonary fibrosis through upregulation of its target, TGF-βRII, and that overexpression of miR-18a-5p might therefore provide a novel approach to the treatment of IPF.

KW - TGF-β1

KW - epithelial-mesenchymal transition

KW - fibrosis

KW - miR-18a

KW - pleural mesothelial cells

UR - http://www.scopus.com/inward/record.url?scp=85016275490&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016275490&partnerID=8YFLogxK

U2 - 10.1016/j.ymthe.2016.12.017

DO - 10.1016/j.ymthe.2016.12.017

M3 - Article

C2 - 28131417

AN - SCOPUS:85016275490

VL - 25

SP - 728

EP - 738

JO - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 3

ER -