Up-Regulated miR-133a Orchestrates Epithelial-Mesenchymal Transition of Airway Epithelial Cells

Authors

Linjie Chen, Creighton University
Xiaobai He, Jiangsu University of Science and Technology
Yan Xie, Creighton University
Yapei Huang, Creighton University
Dennis Wolff, Kansas City University
Peter W. Abel, Creighton University
Yaping Tu, Creighton University

Document Type

Article

Publication Title

Scientific Reports

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.

DOI

10.1038/s41598-018-33913-x

Publication Date

10-19-2018

ISSN

2045-2322

Recommended Citation

Chen L, He X, Xie Y, Huang Y, Wolff D, Abel PW, Tu Y. Up-Regulated miR-133a Orchestrates Epithelial-Mesenchymal Transition of Airway Epithelial Cells. Scientific Reports. 2018; 8(1). doi: 10.1038/s41598-018-33913-x.