Oncotarget

Research Papers:

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

Elena Alexandrova, Giovanni Nassa, Giacomo Corleone, Anton Buzdin, Alexander M. Aliper, Nadezhda Terekhanova, Denis Shepelin, Alexander Zhavoronkov, Michael Tamm, Luciano Milanesi, Nicola Miglino, Alessandro Weisz, Pieter Borger _

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Oncotarget. 2016; 7:25150-25161. https://doi.org/10.18632/oncotarget.7209

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Abstract

Elena Alexandrova1,2, Giovanni Nassa1, Giacomo Corleone1, Anton Buzdin3,4, Alexander M. Aliper3,4, Nadezhda Terekhanova4, Denis Shepelin4,5, Alexander Zhavoronkov6, Michael Tamm7, Luciano Milanesi8, Nicola Miglino7,*, Alessandro Weisz1,9 and Pieter Borger7,*

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

* These authors have contributed equally to this work

Correspondence to:

Pieter Borger, email:

Alessandro Weisz, email:

Keywords: asthma, smooth muscle cells, signalling pathways, CAGE

Received: December 07, 2015 Accepted: January 26, 2016 Published: February 05, 2016

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.

Author Information

Elena Alexandrova

Giovanni Nassa

Giacomo Corleone

Anton Buzdin

Alexander M. Aliper

Nadezhda Terekhanova

Denis Shepelin

Alexander Zhavoronkov

Michael Tamm

Luciano Milanesi

Nicola Miglino

Alessandro Weisz

Pieter Borger
Primary Contact  _


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