Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation ( PVT1 ) as a novel regulator of the asthmatic phenotype in human airway smooth muscle

• Published in: Journal of allergy and clinical immunology 2017-03, Vol.139 (3), p.780-789
• Main Authors: Austin, Philip J., MSc, Tsitsiou, Eleni, PhD, Boardman, Charlotte, MD, Jones, Simon W., PhD, Lindsay, Mark A., PhD, Adcock, Ian M., PhD, Chung, Kian Fan, MD, PhD, Perry, Mark M., PhD
• Format: Article
• Language: English
• Subjects: Adult; Airway management; airway smooth muscle; Allergy and Immunology; Asthma; Asthma - genetics; Asthma - metabolism; Asthma - physiopathology; Asthma and Lower Airway Disease; Female; Genotype & phenotype; Humans; IL-6; Interleukin-6 - genetics; long noncoding RNA; Male; MicroRNAs; Middle Aged; Myocytes, Smooth Muscle - metabolism; Oligonucleotide Array Sequence Analysis; Phenotype; proliferation; Proto-Oncogene Proteins c-myc - genetics; PVT1; Regulation; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Smooth muscle; Software; Transcription, Genetic; Transcriptome; Young Adult
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.06.014

Background The mechanism underlying nonsevere and severe asthma remains unclear, although it is commonly associated with increased airway smooth muscle (ASM) mass. Long noncoding RNAs (lncRNAs) are known to be important in regulating healthy primary airway smooth muscle cells (ASMCs), whereas changed expression has been observed in CD8 T cells from patients with severe asthma. Methods Primary ASMCs were isolated from healthy subjects (n = 9) and patients classified as having nonsevere (n = 9) or severe (n = 9) asthma. ASMCs were exposed to dexamethasone and FCS. mRNA and lncRNA expression was measured by using a microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine relevant biological pathways. Finally, the lncRNA plasmacytoma variant translocation 1 (PVT1) was inhibited by transfection of primary ASMCs with small interfering RNAs, and the effect on ASMC phenotype was examined. Results The mRNA expression profile was significantly different between patient groups after exposure to dexamethasone and FCS, and these were associated with biological pathways that might be relevant to the pathogenesis of asthma, including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in lncRNA expression, yet the expression of only one lncRNA (PVT1) is decreased in patients with corticosteroid-sensitive nonsevere asthma and increased in patients with corticosteroid-insensitive severe asthma. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASMCs from patients with severe asthma. Conclusions lncRNAs are associated with the aberrant phenotype observed in ASMCs from asthmatic patients. Targeting PVT1 might be effective in reducing airway remodeling in asthmatic patients.