Small RNA profiling reveals deregulated phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway in bronchial smooth muscle cells from asthmatic patients

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• 作者：Elena Alexandrova ; PhD^a ; ^b ; Nicola Miglino ; PhD^c ; Adnan Hashim ; PhD^a ; Giovanni Nassa ; PhD^a ; Claudia Stellato ; PhD^a ; Michael Tamm ; MD^c ; Florent Baty ; PhD^d ; Martin Brutsche ; MD ; PhD^d ; Alessandro Weisz ; MD^a ; ^e ; ^{aweisz@unisa.it" class="auth_mail" title="E-mail the corresponding author} ; Pieter Borger ; PhD^c ; ^{pieter.borger@unibas.ch" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Small noncoding RNA ; asthma ; smooth muscle cells ; phosphatase and tensin homolog/phosphoinositide 3-kinase/Akt pathway
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：137
• 期：1
• 页码：58-67
• 全文大小：2053 K

文摘

Aberrant expression of small noncoding RNAs (sncRNAs), microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) in particular, define several pathologic processes. Asthma is characterized by airway hyperreactivity, chronic inflammation, and airway wall remodeling. Asthma-specific miRNA profiles were reported for bronchial epithelial cells, whereas sncRNA expression in asthmatic bronchial smooth muscle (BSM) cells is almost completely unexplored.

Objective

We sought to determine whether the primary BSM sncRNA expression profile is altered in asthmatic patients and identify targets of differentially expressed sncRNAs.

Methods

Small RNA sequencing was used for sncRNA profiling in BSM cells (from 8 asthmatic and 6 nonasthmatic subjects). sncRNA identification and differential expression analysis was performed with iMir software. Experimentally validated miRNA targets were identified by using Ingenuity Pathway Analysis, and putative piRNA targets were identified by using miRanda software.

Results

BSM cells from asthmatic patients showed abnormal expression of 32 sncRNAs (26 miRNAs, 5 piRNAs, and 1 small nucleolar RNA). Target prediction for deregulated miRNAs and piRNAs revealed experimentally validated and predicted mRNA targets expressed in the BSM cells. Thirty-eight of these mRNAs represent major targets for deregulated miRNAs and might play important roles in the pathophysiology of asthma. Interestingly, 6 of these mRNAs were previously associated with asthma, considered as novel therapeutic targets for treatment of this disease, or both. Signaling pathway analysis revealed involvement of 38 miRNA-targeted mRNAs in increased cell proliferation through phosphatase and tensin homolog and phosphoinositide 3-kinase/Akt signaling pathways.

Conclusions

BSM cells of asthmatic patients are characterized by aberrant sncRNA expression that recapitulates multiple pathologic phenotypes of these cells.