MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium

Abstract

We have shown that smoking impacts bronchial airway gene expression and that heterogeneity in this response associates with smoking-related disease risk. In this study, we sought to determine whether microRNAs (miRNAs) play a role in regulating the airway gene expression response to smoking. We examined whole-genome miRNA and mRNA expression in bronchial airway epithelium from current and never smokers (n ‫؍‬ 20) and found 28 miRNAs to be differentially expressed (P < 0.05) with the majority being down-regulated in smokers. We further identified a number of mRNAs whose expression level is highly inversely correlated with miRNA expression in vivo. Many of these mRNAs contain potential binding sites for the differentially expressed miRNAs in their 3 -untranslated region (UTR) and are themselves affected by smoking. We found that either increasing or decreasing the levels of mir-218 (a miRNA that is strongly affected by smoking) in both primary bronchial epithelial cells and H1299 cells was sufficient to cause a corresponding decrease or increase in the expression of predicted mir-218 mRNA targets, respectively. Further, mir-218 expression is reduced in primary bronchial epithelium exposed to cigarette smoke condensate (CSC), and alteration of mir-218 levels in these cells diminishes the induction of the predicted mir-218 target MAFG in response to CSC. These data indicate that mir-218 levels modulate the airway epithelial gene expression response to cigarette smoke and support a role for miRNAs in regulating host response to environmental toxins.cigarette smoke ͉ mir-218 ͉ bronchial airway epithelium

Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects

“…Exposure to cigarette smoke caused down-regulation of some miRNAs in mouse and rat lungs (Izzotti et al, 2009a(Izzotti et al, , 2009b, and the down-regulation in mouse lung was reversed by smoking cessation (Izzotti et al, 2011). Similar findings have been reported in humans; the levels of several miRNAs in airway epithelium (Schembri et al, 2009), placenta (Maccani et al, 2010, and alveolar macrophages (Graff et al, 2012) were lower in smokers than in non-smokers. These results lead us to speculate that miRNAs in tissues, including trachea and lung, exposed to cigarette smoke might leak into blood.…”

A microRNA network regulates expression and biosynthesis of wild-type and ΔF508 mutant cystic fibrosis transmembrane conductance regulator

“…The effector functions of miRNAs in several facets of pulmonary biology have been identified (3)(4)(5), but their actions in airway epithelia are just emerging (6)(7)(8). Although there is no established role for miRNAs in the regulation of fluid and electrolyte transport in the airways, this process is vital to homeostasis and is often perturbed in disease states.…”

MicroRNAs from biology to future pharmacotherapy: Regulation of cytochrome P450s and nuclear receptors

“…Arsenite, which is known to activate nuclear factor-erythroid 2-related factor 2 (Nrf2) (Aono et al, 2003), affects miRNA expression in human lymphoblastoid TH-6 cells (Marsit et al, 2006). Cigarette smoking causes the down-regulation of many miRNAs in the lungs of both mice and rats (Izzotti et al, 2011) as well as human airway epithelial cells (Schembri et al, 2009). The administration of the hepatotoxicants acetaminophen or carbon tetrachloride to rats caused changes in the expression of some miRNAs (there were only 13 commonly changed miRNAs in the two groups) in liver (Fukushima et al, 2007).…”