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Oncotarget. 2016 May 3;7(18):25150-61. doi: 10.18632/oncotarget.7209.

Large-scale profiling of signalling pathways reveals an asthma specific signature in bronchial smooth muscle cells.

Author information

1
Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi (SA), Italy.
2
Genomix4Life Srl, Campus of Medicine, University of Salerno, Baronissi (SA), Italy.
3
Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
4
Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
5
Group for Genomic Regulation of Cell Signalling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
6
Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
7
Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
8
Institute of Biomedical Technologies, National Research Council, Segregate (MI), Italy.
9
Molecular Pathology and Medical Genomics Unit, 'SS. Giovanni di Dio e Ruggi d'Aragona - Schola Medica Salernitana' University Hospital, Salerno (SA), Italy.

Abstract

BACKGROUND:

Bronchial smooth muscle (BSM) cells from asthmatic patients maintain in vitro a distinct hyper-reactive ("primed") phenotype, characterized by increased release of pro-inflammatory factors and mediators, as well as hyperplasia and/or hypertrophy. This "primed" phenotype helps to understand pathogenesis of asthma, as changes in BSM function are essential for manifestation of allergic and inflammatory responses and airway wall remodelling.

OBJECTIVE:

To identify signalling pathways in cultured primary BSMs of asthma patients and non-asthmatic subjects by genome wide profiling of differentially expressed mRNAs and activated intracellular signalling pathways (ISPs).

METHODS:

Transcriptome profiling by cap-analysis-of-gene-expression (CAGE), which permits selection of preferentially capped mRNAs most likely to be translated into proteins, was performed in human BSM cells from asthmatic (n=8) and non-asthmatic (n=6) subjects and OncoFinder tool were then exploited for identification of ISP deregulations.

RESULTS:

CAGE revealed >600 RNAs differentially expressed in asthma vs control cells (p≤0.005), with asthma samples showing a high degree of similarity among them. Comprehensive ISP activation analysis revealed that among 269 pathways analysed, 145 (p<0.05) or 103 (p<0.01) are differentially active in asthma, with profiles that clearly characterize BSM cells of asthmatic individuals. Notably, we identified 7 clusters of coherently acting pathways functionally related to the disease, with ISPs down-regulated in asthma mostly targeting cell death-promoting pathways and up-regulated ones affecting cell growth and proliferation, inflammatory response, control of smooth muscle contraction and hypoxia-related signalization.

CONCLUSIONS:

These first-time results can now be exploited toward development of novel therapeutic strategies targeting ISP signatures linked to asthma pathophysiology.

KEYWORDS:

CAGE; asthma; signalling pathways; smooth muscle cells

PMID:
26863634
PMCID:
PMC5039037
DOI:
10.18632/oncotarget.7209
[Indexed for MEDLINE]
Free PMC Article

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