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

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.

SUBMITTER: Chen L

PROVIDER: S-EPMC6195555 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Chen Linjie L He Xiaobai X Xie Yan Y Huang Yapei Y Wolff Dennis W DW Abel Peter W PW Tu Yaping Y

Scientific reports 20181019 1

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 smoker ...[more]

PMID: 30341388

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Project description:BackgroundChronic obstructive pulmonary disease (COPD) is a common respiratory disease with high morbidity and mortality. The most important pathophysiological change of COPD is airway obstruction. Airway obstruction can cause airflow restriction and obstructive ventilation dysfunction. Currently, many studies have shown that there is EMT phenomenon in the process of airway remodeling of COPD. Cullin4A (CUL4A) is an E3 ubiquitin ligase that interacts with other factors to form the E3 complex. Studies have shown that CLU4A is associated with EMT in non-small cell lung cancer and other cancers. However, its relationship with EMT in COPD has not been reported systematically. In this study, we detected the expression of CUL4A in lung epithelium of COPD patients. In addition, the regulatory effect and mechanism of CUL4A on EMT in COPD were clarified in small airway epithelial cells.MethodsThe expression of CUL4A was assessed by immunohistochemistry in lung epithelium specimens from smokers, non-smokers and patients with chronic obstructive pulmonary disease. The role of CUL4A on cigarette smoke extract (CSE)-induced epithelial-mesenchymal transition (EMT) in human small airway epithelial cells (HSAEpiCs) was assessed by silencing or overexpression CUL4A in vitro. Cigarette smoke is recognized as a high-risk factor in the induction of COPD, and its damage to the airway involves airway damage, airway inflammation and airway remodeling.ResultsThe results shown that CUL4A expression in small airway epithelium was significantly increased in patients with COPD. We also observed a significant negative association between CUL4A and FEV1%, a useful clinical marker for the diagnosis and evaluation of COPD severity, in small airway epithelial cells. In vitro, CSE-induced EMT is associated with high expression of CUL4A, and targeted silencing of CUL4A with shRNA inhibits CSE-induced EMT in human small airway epithelial cells.ConclusionsOur results showed that CUL4A was overexpressed in lung epithelium of COPD patients, and CUL4A could regulate EMT of human small airway epithelium, which revealed a new mechanism of remodeling of small airway epithelium of COPD patients.

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

Publications

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

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