MicroRNA-34c is associated with emphysema severity and modulates SERPINE1 expression

Abstract

BackgroundMicroRNAs (MiRNA) are small non-coding RNAs that regulate gene expression. The aim of this study was to identify miRNAs differentially expressed between mild and moderately emphysematous lung, as well as their functional target mRNAs. Resected lung from patients with COPD undergoing lung cancer surgery was profiled using miRNA (Agilent Human miRNA profiler G4470 V1.01) and mRNA (OperonV2.0) microarrays. Cells of lung origin (BEAS-2B and HFL1) were profiled using mRNA microarrays (Illumina HumanHT-12 V3) after in vitro manipulation.ResultsCOPD patients had mean (SD) age 68 (6) years, FEV1 72 (17)% predicted and gas transfer (KCO) 70 (10)% predicted. Five miRNAs (miR-34c, miR-34b, miR-149, miR-133a and miR-133b) were significantly down-regulated in lung from patients with moderate compared to mild emphysema as defined by gas transfer (p < 0.01). In vitro upregulation of miR-34c in respiratory cells led to down-regulation of predicted target mRNAs, including SERPINE1, MAP4K4, ZNF3, ALDOA and HNF4A. The fold change in ex-vivo expression of all five predicted target genes inversely correlated with that of miR-34c in emphysematous lung, but this relationship was strongest for SERPINE1 (p = 0.05).ConclusionDifferences in miRNA expression are associated with emphysema severity in COPD patients. MiR-34c modulates expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue.

Shifting from Correlation to Causation: Challenges for the Future of Unbiased Molecular Studies in Inflammatory Lung Disease

“…Dres and colleagues (6) measured Ptr,stim as a surrogate for transdiaphragmatic twitch pressure (Pdi,stim). Laghi and colleagues (12) measured Pdi,stim directly (although Ptr,stim and Pdi,stim are correlated [13,14]). Of greater importance than what was measured, is how it was measured and how it was verified.…”

“…To obtain accurate twitch pressures, stimulating probes must be in close proximity to the phrenic nerves (12). Rigorous strategy is imperative to achieve this goal: one nerve is stimulated at a time while monitoring electromyography and pressure (13,14). Once the probe has been positioned where it elicits the strongest signal, investigators repeat the process on the other phrenic nerve.…”

“…Many miRNAs are differentially expressed in lung tissue, airway epithelium, sputum, and blood in COPD (10)(11)(12)(13)(14)(15). Although identifying which miRNAs are perturbed in lung disease is relatively easy, identifying the regulatory role of these miRNAs remains a challenge.…”

Integration of multi-microarray datasets to identify chronic obstructive pulmonary disease-related miRNAs

“…Recently, a COPD study that focused on the screening of serum miRNAs found that miR-34c-5p is significantly dys-regulated in COPD patients as compared to the healthy controls [17]. In addition, miR-34c modulates the expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue [18].…”

Peculiarities of placental microRNA expression in pregnancies complicated by gestational diabetes mellitus and preeclampsia

“…Снижение уровня miR-34c в плацентар-ной ткани ведет к повышению экспрессии гена PAI1 [17]. Это может вызывать снижение инвазии трофобласта на ранних сроках бере-менности и повышение свертываемости крови, обусловливая ухудшение маточно-плацентар-ного кровотока, отложения фибрина в маточ-ных сосудах и микроциркуляторном русле пла-центы, то есть способствовать развитию ПЭ.…”