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Micrornas As Modulators of Smoking-Induced Gene Expression Changes in Human Airway Epithelium

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Micrornas As Modulators of Smoking-Induced Gene Expression Changes in Human Airway Epithelium MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium Frank Schembria,1, Sriram Sridharb,1, Catalina Perdomoc, Adam M. Gustafsond, Xiaoling Zhangd, Ayla Ergune, Jining Lua, Gang Liua, Xiaohui Zhanga, Jessica Bowersf, Cyrus Vazirib, Kristen Ottc, Kelly Sensingerf, James J. Collinse, Jerome S. Brodya, Robert Gettsf, Marc E. Lenburga,b,d, and Avrum Spiraa,b,d,2 aPulmonary Center, bDepartment of Pathology and Laboratory Medicine, and cGenetics and Genomics Graduate Program, Boston University School of Medicine, Boston, MA 02118; dBioinformatics Program, Boston University School of Engineering, Boston, MA 02215; eDepartment of Biomedical Engineering and Center for BioDynamics and Howard Hughes Medical Institute, Boston University, Boston, MA 02215; and fGenisphere, Inc., Hatfield, PA 19440 Edited by Charles R. Cantor, Sequenom Inc., San Diego, CA, and approved November 21, 2008 (received for review July 3, 2008) We have shown that smoking impacts bronchial airway gene Hundreds of human miRNAs have been cloned (11), with each of expression and that heterogeneity in this response associates with them predicted to regulate hundreds of genes by complementary smoking-related disease risk. In this study, we sought to determine binding to the 3Ј-untranslated region (UTR) of target mRNAs (12). whether microRNAs (miRNAs) play a role in regulating the airway A number of miRNAs have been shown to play important roles in gene expression response to smoking. We examined whole-ge- developmental timing, cell death, carcinogenesis, and stress responses in nome miRNA and mRNA expression in bronchial airway epithelium vitro (13–16), such as hypoxia (17). Whereas miRNA expression has and found 28 miRNAs to been examined in lung tumors (18–24), neither the expression of (20 ؍ from current and never smokers (n be differentially expressed (P < 0.05) with the majority being miRNA in bronchial epithelium nor the effect of smoking on bronchial down-regulated in smokers. We further identified a number of airway miRNA expression has been characterized, and it is unclear mRNAs whose expression level is highly inversely correlated with what role miRNAs play in regulating the physiological response to miRNA expression in vivo. Many of these mRNAs contain potential environmental exposures such as tobacco smoke. binding sites for the differentially expressed miRNAs in their In this study, we have profiled the miRNAs expressed in a 3؅-untranslated region (UTR) and are themselves affected by smok- relatively pure population of bronchial airway epithelial cells and ing. We found that either increasing or decreasing the levels of identified those that are differentially expressed with smoking. MEDICAL SCIENCES mir-218 (a miRNA that is strongly affected by smoking) in both Additionally, by whole-genome profiling of both miRNA and primary bronchial epithelial cells and H1299 cells was sufficient to mRNA from the same in vivo samples, we have identified mRNAs cause a corresponding decrease or increase in the expression of that are potentially regulated by smoking-induced changes in predicted mir-218 mRNA targets, respectively. Further, mir-218 miRNA expression. Through in vitro transfection experiments, we expression is reduced in primary bronchial epithelium exposed to have shown that modulating the expression of one such miRNA cigarette smoke condensate (CSC), and alteration of mir-218 levels (mir-218) is sufficient to alter the expression of a subset of the in these cells diminishes the induction of the predicted mir-218 mRNAs that are both predicted targets of this miRNA and altered target MAFG in response to CSC. These data indicate that mir-218 by smoking in vivo. Further, we have shown that cigarette smoke levels modulate the airway epithelial gene expression response to condensate (CSC) suppresses the expression of mir-218 in primary cigarette smoke and support a role for miRNAs in regulating host bronchial epithelial cells and that altering the levels of mir-218 in response to environmental toxins. these cells attenuates the CSC-dependent induction of mir-218 target mRNAs. These studies suggest that smoking-dependent cigarette smoke ͉ mir-218 ͉ bronchial airway epithelium changes in miRNA expression levels mediate some of the smoking- induced gene expression changes in airway epithelium and that pproximately 1.3 billion people smoke cigarettes worldwide, miRNAs might therefore play a role in the host response to Awhich contributes to 5 million preventable deaths per year (1). environmental exposures and the pathogenesis of smoking-related Smoking is a significant risk factor for lung cancer (2), the leading lung disease. cause of cancer-related death in the United States, and chronic Results obstructive pulmonary disease (COPD), the fourth leading cause of death worldwide. Cigarette smoking has been found to induce a Smoking Affects Expression of miRNAs in Bronchial Epithelium. Mi- number of genetic and molecular changes in the respiratory tract, croRNA and mRNA expression levels in bronchial epithelial RNA including cellular atypia (3), loss of heterozygosity (4, 5), and collected from 20 volunteers (10 current smokers, 10 never smok- promoter hypermethylation (6), which can occur in cytologically ers) recruited for this study were determined by using microarrays normal airway epithelium (5, 7). We have characterized the effects [supporting information (SI) Fig. S1]. Demographic data for these of smoking on the human airway epithelial transcriptome and found subjects are presented in Table 1. After miRNA microarray data that smoking induces expression of airway genes involved in reg- preprocessing (Fig. S2A), 232 miRNAs were detected above back- ulation of oxidant stress, xenobiotic metabolism, and oncogenesis while suppressing those involved in regulation of inflammation and Author contributions: F.S., S.S., J.L., J.J.C., J.S.B., R.G., M.E.L., and A.S. designed research; tumor suppression (8). In addition, we have described a pattern of F.S., S.S., C.P., G.L., Xiaohui Zhang, J.B., K.O., K.S., and A.S. performed research; A.M.G., J.B., gene expression in cytologically normal large airway epithelial cells C.V., K.S., and R.G. contributed new reagents/analytic tools; F.S., S.S., C.P., A.M.G., Xiaoling that can serve as a biomarker for lung cancer elsewhere in the lung Zhang, A.E., M.E.L., and A.S. analyzed data; and F.S., S.S., M.E.L., and A.S. wrote the paper. (9). These studies suggest that gene expression changes in airway The authors declare no conflict of interest. epithelium reflect host response to and damage from cigarette This article is a PNAS Direct Submission. smoke; however, the regulatory mechanisms mediating these gene 1F.S. and S.S. contributed equally to this work. expression changes are unclear. 2To whom correspondence should be addressed at: Boston University, 715 Albany Street, MicroRNAs (miRNA) are small noncoding RNAs that serve to R304, Boston, MA 02118. E-mail: [email protected]. down-regulate gene expression by suppression of translation or This article contains supporting information online at www.pnas.org/cgi/content/full/ messenger RNA (mRNA) degradation. Thirty percent of protein- 0806383106/DCSupplemental. coding genes are predicted to be regulated by miRNAs (10). © 2009 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806383106 PNAS Early Edition ͉ 1of6 Downloaded by guest on October 2, 2021 Table 1. Patient demographics A Smokers (Array) Smokers (PCR) * p < 0.05 ** p < 0.01 Current smokers Never smokers P value Non smokers (Array) Non smokers (PCR) n 10 10 6 ** 14 Age 37.2 Ϯ 9.9 31.2 Ϯ 10 0.20 5 12 ** ** Race 5 AFA, 4 HIS, 1 CAU 3 AFA, 2 HIS, 5 CAU 0.15 10 4 ** Sex 7 M, 3 F 3 M, 7 F 0.07 8 3 Ϯ 6 Pack years 18.8 16 0 0.0002 2 4 1 Demographics for individuals recruited for bronchoscopy are listed above. 2 Relative Expression P values for sex (M, male; F, female) and race (AFA, African-American; HIS, Relative Expression 0 0 mir-218 mir-128b Hispanic; CAU, Caucasian) were calculated by using Fisher’s exact test. Stan- (n = 8, 4 smokers v. 4 non smokers) (n = 6, 3 smokers v. 3 non smokers) dard deviations for age and pack years are listed. P values for age and pack years were calculated by using Student’s t test. 6 ** 10 5 9 * 8 4 7 ground and the expression of these miRNAs was analyzed further. 6 3 Temporal (3 months) and technical replicates run on miRNA * 5 2 4 arrays were highly reproducible across these 232 detected miRNAs, 3 * 1 2 Relative Expression 2 Relative Expression with the temporal replicates having an R ϭ 0.91 and technical 1 0 2 0 replicates having an R ϭ 0.94. Principal component analysis of all mir-181d mir-500 232 detected miRNAs demonstrates modest separation of subjects (n = 7, 4 smokers v. 3 non smokers) (n = 7, 3 smokers v. 4 non smokers) by smoking status (Fig. S3), suggesting that smoking impacts miRNA expression in bronchial epithelium. Using a Welch’s t test, B 1.40 28 miRNAs were found to be differentially expressed between 1.20 current and never smokers (P Ͻ 0.05), which is Ϸ3 times more than 1.00 Untreated (n=4) is expected by chance at that threshold (Fig. 1, Table S1). Of these 0.80 DMSO-treated (n=6) 28 miRNAs, 23 were down-regulated in smokers. The most signif- 0.60 ϭ ϫ Ϫ4 CSC-treated (n=5) icantly altered miRNA was mir-218 (P 5 10 ), which was 0.40 down-regulated 4-fold in smokers. Four of the top differentially Relative Expression 0.20 expressed miRNAs (mir-218, mir-128b, mir-500, and mir-181d) 0.00 were validated in a subset of bronchial samples by using quantitative (q)RT-PCR (Fig.
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