Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle.
Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle.
复制标题
DOI：
10.1016/j.jaci.2016.06.014
复制
发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Perry MM
中科院分区：
文献类型：
--
作者：
Austin PJ;Tsitsiou E;Boardman C;Jones SW;Lindsay MA;Adcock IM;Chung KF;Perry MM
非重度和重度哮喘的潜在机制尚不清楚，尽管它通常与气道平滑肌（ASM）质量增加有关。已知长链非编码RNA（lncRNA）在调节健康的初级气道平滑肌细胞（ASMC）中是重要的，而在患有严重哮喘的患者的CD 8 T细胞中观察到改变的表达。从健康受试者（n = 9）和归类为非重度（n = 9）或重度（n = 9）哮喘的患者中分离原代ASMC。ASMCs暴露于地塞米松和FCS。mRNA和lncRNA表达通过使用微阵列和定量实时PCR测量。生物信息学分析用于检查相关的生物学途径。最后，通过用小干扰RNA转染原代ASMC来抑制lncRNA浆细胞瘤变体易位1（PVT 1），并检查对ASMC表型的影响。暴露于地塞米松和FCS后，患者组之间的mRNA表达谱存在显著差异，这些差异与可能与哮喘发病机制相关的生物学途径相关，包括细胞增殖和与糖皮质激素活性相关的途径。我们还观察到lncRNA表达的显著变化，但只有一种lncRNA（PVT 1）的表达在皮质类固醇敏感的非重度哮喘患者中降低，而在皮质类固醇不敏感的重度哮喘患者中升高。随后的靶向研究证明了这种lncRNA在控制重度哮喘患者ASMC增殖和IL-6释放方面的重要性。lncRNA与哮喘患者ASMC中观察到的异常表型相关。靶向PVT 1可能有效地减少哮喘患者的气道重塑。
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. 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. 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. 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.