Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells

Linjie Chen, Xiaobai He, Yan Xie, Yapei Huang, Dennis W. Wolff, Peter W. Abel, Yaping Tu

Research output: Contribution to journalArticle

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Abstract

Dysregulation of microRNAs (miRNAs) contributes to epithelial-mesenchymal transition (EMT) of cancer, but the pathological roles of miRNAs in airway EMT of lung diseases remains largely unknown. We performed sequencing and real-time PCR analysis of the miRNA expression profile of human airway epithelial cells undergoing EMT, and revealed miR-133a to be one of the most common up-regulated miRNAs. MiR-133a was previously reported to be persistently up-regulated in airway epithelial cells of smokers. We found that mice exposed to cigarette smoke (CS) showed airway hyper-responsiveness, a typical symptom occurring in CS-related lung diseases, up-regulation of miR-133a and EMT marker protein N-cadherin in airway epithelium. Importantly, miR-133a overexpression induces airway epithelial cells to undergo spontaneous EMT via down-regulation of grainyhead-like 2 (GRHL2), an epithelial specific transcriptional factor. Loss of GRHL2 causes down-regulation of epithelial splicing regulatory protein 1 (ESRP1), a central coordinator of alternative splicing processes that are critical in the regulation of EMT. Down-regulation of ESRP1 induces isoform switching of adherens junction-associated protein p120-catenin, and leads to the loss of E-cadherin. Our study is the first to demonstrate that up-regulated miR-133a orchestrates airway EMT via alternative splicing processes, which points to novel therapeutic possibilities for the treatment of CS-related lung disease.

Original languageEnglish (US)
Article number15543
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Epithelial-Mesenchymal Transition
Epithelial Cells
MicroRNAs
Smoke
Tobacco Products
Protein Splicing
Lung Diseases
Down-Regulation
Alternative Splicing
Cadherins
Respiratory Hypersensitivity
Adherens Junctions
Real-Time Polymerase Chain Reaction
Protein Isoforms
Up-Regulation
Epithelium
Neoplasms

All Science Journal Classification (ASJC) codes

  • General

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Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells. / Chen, Linjie; He, Xiaobai; Xie, Yan; Huang, Yapei; Wolff, Dennis W.; Abel, Peter W.; Tu, Yaping.

In: Scientific Reports, Vol. 8, No. 1, 15543, 01.12.2018.

Research output: Contribution to journalArticle

Chen, Linjie ; He, Xiaobai ; Xie, Yan ; Huang, Yapei ; Wolff, Dennis W. ; Abel, Peter W. ; Tu, Yaping. / Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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