key: cord-0000474-ft5wl70x
authors: Tomankova, Tereza; Petrek, Martin; Kriegova, Eva
title: Involvement of microRNAs in physiological and pathological processes in the lung
date: 2010-11-23
journal: Respir Res
DOI: 10.1186/1465-9921-11-159
sha: b97de55ba907c3b1f3048bfecf6b2b3970363541
doc_id: 474
cord_uid: ft5wl70x

To date, at least 900 different microRNA (miRNA) genes have been discovered in the human genome. These short, single-stranded RNA molecules originate from larger precursor molecules that fold to produce hairpin structures, which are subsequently processed by ribonucleases Drosha/Pasha and Dicer to form mature miRNAs. MiRNAs play role in the posttranscriptional regulation of about one third of human genes, mainly via degradation of target mRNAs. Whereas the target mRNAs are often involved in the regulation of diverse physiological processes ranging from developmental timing to apoptosis, miRNAs have a strong potential to regulate fundamental biological processes also in the lung compartment. However, the knowledge of the role of miRNAs in physiological and pathological conditions in the lung is still limited. This review, therefore, summarizes current knowledge of the mechanism, function of miRNAs and their contribution to lung development and homeostasis. Besides the involvement of miRNAs in pulmonary physiological conditions, there is evidence that abnormal miRNA expression may lead to pathological processes and development of various pulmonary diseases. Next, the review describes current state-of-art on the miRNA expression profiles in smoking-related diseases including lung cancerogenesis, in immune system mediated pulmonary diseases and fibrotic processes in the lung. From the current research it is evident that miRNAs may play role in the posttranscriptional regulation of key genes in human pulmonary diseases. Further studies are, therefore, necessary to explore miRNA expression profiles and their association with target mRNAs in human pulmonary diseases.

A. miRNA definition, biology and function Discovery of microRNA (miRNA) lin-4 was the first short non-coding RNA discovered in 1993 as a regulator of developmental timing in Caenorhabditis elegans [1] . The first non-coding RNA identified in humans was let-7, which has been found involved in the control of developmental timing in humans and animals [2, 3] . Soon it became evident that these short non-coding RNAs are a part of much larger class of non-coding RNAs and the term microRNA (miRNA) was introduced [4] . To date, more than 900 miRNAs in Homo sapiens have been identified (940 in miRBase v15).

MiRNAs are small non-coding RNAs~22 nucleotides (nt) long involved in the negative post-transcriptional gene regulation via RNA interference mechanism [5, 6] . The sequences of miRNAs are highly conserved among plants-microorganisms-animals, suggesting that miRNAs represent a relatively old and important regulatory pathway [7] . MiRNAs belong to the most abundant class of human gene regulators [8] : up to a third of the human genes are regulated by miRNAs [9] . MiRNAs are, therefore, key regulators of numerous genes in biological processes ranging from developmental timing to apoptosis [e.g. [10] [11] [12] [13] [14] ]. It has been speculated that miRNAs may be associated with the regulation of almost every aspect of cell physiology [8] .

MiRNA genes are localized in the non-coding regions or in the introns of protein-coding genes in the genomic DNA. The miRNA genes are much longer than biologically active, mature miRNAs which originate through a multistep process [15] (Figure 1 ). Briefly, transcription by the RNA polymerase II leads to hundred or thousand nucleotides long primary miRNA transcripts (pri-miRNAs) [16] .

A local stem-loop structure of pri-miRNAs is then cleaved in the nucleus by the dsRNA-specific ribonuclease Drosha/ Pasha to 70 nucleotides long precursor miRNA (pre-miRNA) [17] in a process known as "cropping" [18, 19] . Pre-miRNAs are then actively transported from the nucleus to the cytoplasm [20, 21] . In the cytoplasm, pre-miRNAs are subsequently cleaved by RNase III Dicer into~22-nt miRNA duplexes [17, 20] . One strand of the short-lived miRNA duplex is degraded ("passenger" strand, miR*), whereas the other ("guide", miR) strand is incorporated into the RNA-induced silencing complex (RISC) and serves as a functional, mature miRNA [8] . Selection of the "guide" strand is based on the base pairing stability of both dsRNA ends [22, 23] .

Depending on the complementarity between miRNA and 3' untranslated region (UTR) of target mRNA there are two known mechanisms of miRNAs action on mRNAs: 1) target mRNA degradation and 2) translational inhibition with little or no influence on mRNA levels [24] (Figure 2) . Firstly, the deadenylation and subsequent degradation of the target mRNA occurs when miRNA is near-perfectly complementary with target mRNA [25, 26] . A recent study proved that mRNA degradation represents the major mechanism of miRNA regulation [27] . The authors showed that about 84% of all protein-coding mRNA targets undergo degradation while recognized by their cognate miRNA [27] . Secondly, the translational inhibition MiRNAs are transcribed by RNA polymerase II from the genomic DNA as long (hundred or thousand nucleotides) primary miRNA transcripts (pri-miRNAs). A local stem-loop structure of pri-miRNAs is then cleaved in the nucleus by the dsRNA-specific ribonuclease Drosha/Pasha to produce a 70 nucleotides long precursor miRNA (pre-miRNA). Pre-miRNAs in form of hairpins are then actively transported from the nucleus to the cytoplasm. In the cytoplasm, pre-miRNAs are subsequently cleaved by RNase III Dicer into~22-nt miRNA duplexes, consisting of the "guide" (miR) strand and the "passenger" (miR*) strand. The "passenger" strand is degraded, the "guide" strand is incorporated into the RNA-induced silencing complex (RISC) and serves as a functional, mature miRNA, acting by two different mechanisms according to the complementarity with the target mRNA. Adopted from Kim [15] . occurs when miRNA is only partially complementary to its target mRNA [28] [29] [30] . In light of the recent study by Guo et al [27] , this mechanism does not represent a predominant reason for reduced protein output.

Besides the complementarity between miRNA and mRNA, several other factors may influence the miRNA action such as impaired processing, methylation, gene polymorphisms, gene amplification, deletion of Dicer, translocations and others [31] .

It is evident that single miRNAs may regulate translation of numerous downstream mRNAs and each mRNA is likely to be regulated by several miRNAs simultaneously [30, 32] . Thus, identification of miRNA target genes has been a great challenge [33] . Numerous computational algorithms [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] were established which combined 5' seed matches, thermodynamic stability and conservation analysis in order to maximize specificity when predicting mRNA targets [44] (Table 1) . Nevertheless, various algorithms differ in the selection of mRNA targets and simultaneous application of several algorithms is, therefore, highly recommended. Nowadays, many web-based applications [45] [46] [47] [48] [49] [50] [51] [52] have been developed by combining existing prediction programs with functional annotations associated to many miRNA, gene, protein or biological pathway resources such as miR-Base, Ensembl, Swiss-Prot, UCSC genome browser, KEGG pathway and other databases [44] (Table 2) .

However, because of high similarities in miRNA sequences, computational algorithms may predict a large number of putative miRNA binding sites on mRNA targets [33] . Thus, experimental validation in biological system is fundamental to complete the target prediction [44] ; the currently available methods [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] are listed in Table 3 . Of these, antagomir studies or immunoprecipitation of Ago-bound mRNAs have been specifically developed for miRNA-mRNA studies. Antagomirs represent a novel class of chemically engineered oligonucleotides used to silence endogenous microRNAs [64, 65] . Immunoprecipitation is then based on the observation that each member of the Argonaute (Ago) protein family (catalytic components of the RNA-induced silencing complex) can bind to miRNAs and to partially complementary sequences in the 3'-UTR of specific target mRNAs. Thus, using highly specific monoclonal antibodies against members of the Ago protein family, Ago-bound mRNAs can be co-immunoprecipitated [66, 67] .

The lung has a very specific miRNA expression profile, highly conserved across mammalian species [68, 69] .

However, the knowledge of the role of miRNAs in physiological and pathological conditions in the lung compartment is still limited and it is based mainly on the studies in animal models. MiRNAs have been shown to be involved in 1) the lung development and homeostasis, 2) in inflammation and viral infections and 3) miRNA deregulation may contribute to several pulmonary diseases ( Figure 3 ). Hereby, we summarize the knowledge of the involvement of miRNAs in the lung and current information on their posttranscriptional regulation ongoing in the lung compartment. Besides pathology we pay attention also to physiological lung because understanding miRNA function in normal condition is prerequisite to description of its involvement in disease.

Several miRNAs such as miR-155, miR-26a, let-7, miR-29, miR-15/miR-16, miR-223, miR-146a/b and the miR-17-92 cluster have been shown to be involved in homeostasis and in the lung development ( Table 4 ). The pulmonary role of miR-155 was studied in murine lung, where it has been shown that miR-155 is crucially involved in the differentiation of naive T-cells into Th1 and Th2 cells [70, 71] . Mice deficient in bic/miR-155 became immunodeficient and displayed increased lung remodelling, higher bronchoalveolar leukocytes and impaired T-and B-cell responses to inflammatory stimuli [70] . Another member of miRNA family, miR-26a, has been shown to be selectively expressed in the bronchial and alveolar epithelial cells in murine lung [72] . Target mRNA of miR-26a is the transcription factor SMAD1, which is involved in the regulation of bone morphogenic protein signalling during lung development and pulmonary vascular remodelling [73, 74] . Thus, miR-26a might be important in controlling essential developmental and physiological events in the lung [75] . Also the miR-17-92 cluster is believed to regulate the lung development because its expression is high in embryonic development and steadily declines through development into adulthood [76] . Mice deficient in the miR-17-92 cluster died shortly after birth and lung hypoplasia/ventricular septal defects were demonstrated; moreover the absence of the miR-17-92 cluster let to upregulation of the pro-apoptotic protein Bim and inhibition of B-cell development [77] . On the other side, the overexpression of the miR-17-92 cluster in murine models resulted in an abnormal phenotype manifested by absence of terminal air sacs, which were replaced by highly proliferative, undifferentiated pulmonary epithelium [76] . Other miRNAs found to be involved in the pulmonary homeostasis are members of let-7 family [78] , miR-29 [79] , miR-15 and miR-16 [80, 81] , which Northern blot analysis [54] Quantitative real-time PCR [55] Ribonuclease protection assay [56] in situ hybridization [57] , [58] miRNA mimics [59] Western blot [60] Immunocytochemistry [61] Bead-based flow cytometry method [62] Suppression of miRNA expression in cells by antisense locked-nucleic acid oligonucleotides [63] Antagomir assays [64] , [65] Immunoprecipitation of Ago-bound mRNAs [66] , [67] function as tumor suppressors in lung cells. In addition, another miRNA, miR-223, has been shown to be crucial for normal granulocyte development and function in the lung [82] . MiR-223 mutant mice spontaneously developed neutrophilic lung inflammation with tissue destruction after endotoxin challenge [82] .

Two miRNAs, miR-146a and miR-146b, have been shown to play central role in the negative feedback regulation of IL-1β-induced inflammation; the mechanism is down-regulation of two proteins IRAK1 and TRAF6 involved in Toll/interleukin-1 receptor (TIR) signalling [83, 84] . Also other miRNAs have been shown to regulate the inflammation in mouse lung exposed to aerosolized lipopolysaccharide (LPS): miR-21, -25, -27b, -100, -140, -142-3p, -181c, -187, -194, -214, -223 and -224 [72] . Increase in these miRNAs correlated with the downregulation of pro-inflammatory cytokine production such as TNFα [72] . The deregulation of miR-155, the miR-17-92 cluster and miR-223, miRNAs involved in lung development and homeostasis, resulted in the uncontrolled lung inflammation in murine models [70, 77, 82] . Based on the studies in murine models, there is evidence that miRNA expression may influence also the course of pulmonary viral infections [85, 86] . MiR-200a and miR-223 were detected in lethal influenza virus infection presumably contributing to the extreme miR-155 important for normal lung airway remodelling (A) [70] alteration of T-cell differentiation (A) [71] miR-26a highly expressed within bronchial and alveolar epithelial cells, important for lung development (H) [75] let-7 highly expressed in normal lung tissue, functions as a tumor suppressor in lung cells (H) [78] miR-29 functions as tumor suppressor in lung cells (H) [79] miR-15, miR-16 function as tumor suppressor genes (H) [80] , [81] miR-223 control of granulocyte development and function (A) [82] miR-146a/b central to the negative feedback regulation of IL-1β-induced inflammation (H) [83] , [84] miR-200a, miR-223 contribution to the extreme virulence of the r1918 influenza virus (A) [85] miR-17 family, miR-574-5p, miR-214 upregulated at the onset of SARS infection (A, H) [86] virulence of the r1918 influenza virus [85] . MiR-17 family, miR-574-5p and miR-214 were upregulated at the onset of SARS infection: these miRNAs may help the virus to evade the host immune system and are responsible for effective transmission at the initial stage of viral infection [86] .

There is evidence that upregulation or downregulation of miRNAs is critical for the lung development/homeostasis and thus may contribute to development of pathological pulmonary conditions, namely to smokingrelated diseases including lung cancerogenesis, fibrosis, and other immune-mediated disorders including allergy (Table 5) .

Recent studies have implicated the miRNAs in the pathogenesis of immune system mediated pulmonary diseases. Tan and colleagues [87] described that a single nucleotide polymorphism in the 3'UTR of HLA-G, a known asthma-susceptibility gene, disrupts the binding sites of three miRNAs (miR-148a, miR-148b, miR-152) targeting this gene. Thus, it is likely that the association of the HLA-G gene to asthma-susceptibility may be due to the allele-specific regulation of this gene by miRNAs [87] . MiR-21 is a further miRNA crucially involved in allergic lung inflammation. Its molecular target is IL-12p35, a cytokine contributing to polarization of Th cells toward Th2 cells [88] . MiR-126 is another miRNA found to be involved in the pathogenesis of allergic airways disease [89] . The blockade of miR-126 suppressed the asthmatic phenotype leading to diminished Th2 responses, suppression of inflammation, reduced airways hyperresponsiveness, inhibition of eosinophil recruitment, and lower mucus hypersecretion [89] . In bronchial epithelial cells stimulated with IL-4 and TNFα, let-7, miR-29a and miR-155 have been involved in the regulation of allergic inflammation [90] . Multiple members of let-7 family were also found upregulated in experimental asthma model and the pro-inflammatory role of let-7 miRNAs on the allergic cytokine expression was confirmed [91] . Another study showed that expression of RhoA in bronchial smooth muscle cells (BSMCs), a new target for asthma therapy, is negatively regulated by miR-133a [92] . The same group later revealed that IL-13 is capable of reducing the miR-133a expression in BSMCs and that the miR-133a downregulation causes an Table 5 MiRNAs involved in pathological processes in the lung miRNA Function (A animal studies, H human studies) References miR-155, miR-17-92 cluster deregulation results in uncontrolled inflammation (A) [70] , [71] , [77] miR-21, miR-27b, miR-100, miR-181c, miR-223, miR-224 increased following exposure to LPS (A) [72] miR-155 overexpressed in solid tumors, inhibition of tumor suppressor genes (A, H) [81] miR-223 impaired granulocyte function, regulator of granulocyte production and inflammatory response (A) [82] miR-148a/b, miR-152 allele-specific regulation of asthma susceptibility HLA-G gene (H) [87] miR-21 key role in asthma (A) [88] overexpressed in solid malignancies (A, H) [103] up-regulated in bleomycin-induced fibrosis and IPF (A, H) [110] miR-126 suppression of the asthmatic phenotype by blockade of miR-126 (A) [89] downregulated in cystic fibrosis airway epithelial cells (H) [111] let-7, miR-29a, miR-155 regulation of allergic inflammation in bronchial epithelial cells (A, H) [90] let-7 pro-inflammatory effect in experimental asthma (A) [91] role in lung cancer progression (H) [99] miR-133a regulator of expression of RhoA, target for asthma therapy (A, H) [92] , [93] miR-146a reduced expression in COPD fibroblasts (H) [95] miR-218, miR-15a, miR-199b, miR-125a/b, miR-294 deregulated due to smoking (A, H) [96, 97] miR-218 tumor suppressor in non-small cell lung cancer (H) [98] miR-17-92 cluster overexpressed in lung cancers (H) [102] miR-34 regulation of apoptosis in lung cancer cells (H) [105] [106] [107] miR-210 overexpressed in lung cancer (H) [108] let-7d pro-fibrotic effect in pulmonary fibrosis (A, H) [109] upregulation of RhoA, presumably resulting in an augmentation of the contraction [93] .

Lung cancer and chronic obstructive pulmonary disease (COPD) share a common environmental risk factor in cigarette smoke exposure [94] . Although extensive studies of the involvement of miRNAs in lung cancer have been performed, there are only few reports focused on the role of miRNAs in COPD. Recent study on fibroblasts from COPD subjects stimulated in vitro with pro-inflammatory cytokines released less miR-146a than smokers without COPD [95] . The reduced miR-146a expression resulted in prolonged mRNA half-life of cyclooxygenase-2, thus increasing prostaglandin E2 in fibroblasts from COPD subjects [95] . There is evidence that smoking has influence also on other miRNAs. Expression profiling study in the rats exposed to environmental cigarette smoke revealed 24 downregulated miRNAs (especially let-7 family, miR-10, [96] . MiR-294, a known inhibitor of transcriptional repressor genes, was the only miRNA upregulated in smoke-exposed rats [96] . In another study, bronchial airway epithelial cells from current and never smokers differed in the expression of 28 miRNAs (especially miR-218, miR-15a, miR-199b, miR-125a/b, miR-294) in comparison to smokers, whereas the majority of deregulated miRNAs were downregulated in smokers [97] . Similar observation was observed in lung squamous cell carcinoma, where downregulation of miR-218 was associated with a history of cigarette smoking [98] . However, the majority of miRNA studies in smokingrelated diseases are focused on the role of miRNAs in lung cancer. Altered expression of miR-155 and let-7 has been reported in lung adenocarcinoma and expression of let-7 related to patient survival [99] . Moreover, it has been shown that let-7 may also play a role in lung cancer progression [99] [100] [101] . Further, increased expression of the miR-17-92 cluster has also been detected in lung cancer [102] . Another miRNAs involved in lung cancerogenesis are miR-21 and miR-34 families. MiR-21 was shown to regulate multiple tumor/metastasis suppressor genes in lung solid tumors [103] . MiR-34a/b/c have been identified to be a component of the p53 tumor suppressor network: p53 upregulates in response to DNA damage the members of miR-34 family [104] , thus regulating genes involved in the cell cycle and apoptosis [105] [106] [107] . Furthermore, miR-210 has been overexpressed in late stages of lung cancer, thus mediated mitochondrial alterations associated with modulation of hypoxia-inducible factor-1 activity [108] . Next, miR-218 was identified as a putative tumor suppressor in non-small cell lung cancer [98] .

Recently, it was reported that miRNAs may play pivotal regulatory role also in the fibrotic processes ongoing in the lung: the downregulation of let-7 d in idiopathic pulmonary fibrosis (IPF) resulted in the pro-fibrotic effects [109] . Also, upregulation of miR-21 was reported in the lungs of IPF patients and in the murine lungs with bleomycin-induced fibrosis, whereas miR-21 expression was enhanced by pro-fibrotic TGF-β1 [110] . Another disease associated with miRNA change was cystic fibrosis. Downregulation of miR-126 was detected in cystic fibrosis bronchial epithelial cells and its expression correlated with upregulation of TOM1 mRNA both in vitro and in vivo [111] . TOM1, a miR-126 target, was reported to be involved in the regulation of innate immune responses through its involvement in the TLR2/4 and IL-1β and TNF-α-induced signalling pathways [111] .

Small non-coding RNAs (miRNAs) play pivotal role in the posttranscriptional regulation of numerous human genes, mainly via degradation of target mRNAs. There is evidence that the lung has a very specific miRNA expression profile undergoing changes during the lung development. Studies namely in animal models have provided evidence that miRNAs participate in lung homeostasis and play pivotal role also in the control of pulmonary inflammation and viral infections. Recent studies showed evidence that upregulated or downregulated expression of various miRNAs play an active role in the pathogenesis of pulmonary diseases. Specific miRNA expression profiles were characterized for smoking related-diseases including COPD and lung cancer, immune-mediated pulmonary diseases and pulmonary fibrosis. Moreover, several miRNAs crucial for lung development and homeostasis such as let-7, miR-155 or miR-19-72 cluster have been identified to be deregulated in pulmonary allergy, asthma or lung cancer. The knowledge of altered miRNA expression profiles in diseased lung may thus offer new insights in the biology of pulmonary diseases. Moreover, miRNAs may represent attractive novel diagnostic biomarkers mainly due to their higher stability when compared to mRNAs [112] and could potentially provide possibilities for therapeutic intervention [31, 113, 114] .

Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14

A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA

Control of developmental timing in animals

Glimpses of a tiny RNA world

MicroRNAs: genomics, biogenesis, mechanism, and function

MicroRNAs: small RNAs with a big role in gene regulation

Micro-RNAs: small is plentiful

Advances in microRNAs: implications for immunity and inflammatory diseases

Emerging role of microRNAs in disease pathogenesis and strategies for therapeutic modulation

MicroRNA: past and present

A developmental timing microRNA and its target regulate life span in C. elegans

Mesodermally expressed Drosophila microRNA-1 is regulated by Twist and is required in muscles during larval growth

MicroRNAs and the regulation of cell death

MicroRNA-143 regulates adipocyte differentiation

MicroRNA biogenesis: coordinated cropping and dicing

MicroRNA maturation: stepwise processing and subcellular localization

The nuclear RNase III Drosha initiates microRNA processing

EST analyses predict the existence of a population of chimeric microRNA precursor-mRNA transcripts expressed in normal human and mouse tissues

Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs

Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs

Nuclear export of microRNA precursors

Asymmetry in the assembly of the RNAi enzyme complex

Functional siRNAs and miRNAs exhibit strand bias

Revisiting the principles of microRNA target recognition and mode of action

Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs

MicroRNAs direct rapid deadenylation of mRNA

Mammalian microRNAs predominantly act to decrease target mRNA levels

Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans

The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation

Specificity of microRNA target selection in translational repression

Integrating the MicroRNome into the study of lung disease

Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs

Experimental validation of miRNA targets

MicroRNA targets in Drosophila

Prediction of mammalian microRNA targets

Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets

MicroRNA target predictions across seven Drosophila species and comparison to mammalian targets

A combined computational-experimental approach predicts human microRNA targets

Inference of miRNA targets using evolutionary conservation and pathway analysis

IM: Prediction of both conserved and nonconserved microRNA targets in animals

miTarget: microRNA targetgene prediction using a support vector machine

Rigoutsos I: A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes

Fast and effective prediction of microRNA/target duplexes

Got target? Computational methods for microRNA target prediction and their extension

Human microRNA target analysis and gene ontology clustering by GOmir, a novel stand-alone application

miRDB: A microRNA target prediction and functional annotation database with a wiki interface

MiRecords: an integrated resource for microRNA-target interactions

miRGator: an integrated system for functional annotation of microRNAs

Huang HD: miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes

MirZ: an integrated microRNA expression atlas and target prediction resource

MicroRNA and mRNA integrated analysis (MMIA): a web tool for examining biological functions of microRNA expression

The database of experimentally supported targets: a functional update of TarBase

MicroRNA-155 regulates human angiotensin II type 1 receptor expression in fibroblasts

Computational prediction and experimental validation of Ciona intestinalis microRNA genes

Potential mRNA degradation targets of hsa-miR-200c, identified using informatics and qRT-PCR

Identification and characterization of microRNAs from the bovine adipose tissue and mammary gland

The human angiotensin II type 1 receptor +1166 A/C polymorphism attenuates microrna-155 binding

In situ detection of animal and plant microRNAs

hsa-miR-520 h downregulates ABCG2 in pancreatic cancer cells to inhibit migration, invasion, and side populations

A strategy to rapidly identify the functional targets of microRNAs by combining bioinformatics and mRNA cytoplasmic/nucleic ratios in culture cells

Widespread deregulation of microRNA expression in human prostate cancer

MicroRNA expression profiles classify human cancers

A cellular microRNA mediates antiviral defense in human cells

Antagomir-17-5p abolishes the growth of therapy-resistant neuroblastoma through p21 and BIM

Silencing of microRNAs in vivo with 'antagomirs'

Identification of human microRNA targets from isolated argonaute protein complexes

Isolation of microRNA targets by miRNP immunopurification

Maternally imprinted microRNAs are differentially expressed during mouse and human lung development

microRNA expression in the aging mouse lung

Requirement of bic/microRNA-155 for normal immune function

Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells

Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids

Smad1 expression and function during mouse embryonic lung branching morphogenesis

Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension

MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy

Transgenic overexpression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells

Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters

The let-7 microRNA represses cell proliferation pathways in human cells

MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B

MicroRNA signatures in human cancers

A microRNA expression signature of human solid tumors defines cancer gene targets

Regulation of progenitor cell proliferation and granulocyte function by microRNA-223

NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses

Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells

MicroRNA expression and virulence in pandemic influenza virus-infected mice

MicroRNome analysis unravels the molecular basis of SARS infection in bronchoalveolar stem cells

Allele-specific targeting of microRNAs to HLA-G and risk of asthma

MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression

Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease

Coordinated changes in mRNA turnover, translation, and RNA processing bodies in bronchial epithelial cells following inflammatory stimulation

Pro-inflammatory role for let-7 microRNAs in experimental asthma

Down-regulation of miR-133a contributes to up-regulation of Rhoa in bronchial smooth muscle cells

MicroRNAs and Their Therapeutic Potential for Human Diseases: MiR-133a and Bronchial Smooth Muscle Hyperresponsiveness in Asthma

Mechanisms involved in lung cancer development in COPD

Reduced MiR-146a Increases Prostaglandin E2 in Chronic Obstructive Pulmonary Disease Fibroblasts

Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke

MicroRNAs as modulators of smokinginduced gene expression changes in human airway epithelium

MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma

Unique microRNA molecular profiles in lung cancer diagnosis and prognosis

Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival

RAS is regulated by the let-7 microRNA family

A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation

MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene

A microRNA component of the p53 tumour suppressor network

Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest

The miR-34 family in cancer and apoptosis

microRNAs and lung cancer: tumors and 22-mers

is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity

Inhibition and Role of let-7 d in Idiopathic Pulmonary Fibrosis

mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis

Greene CM: miR-126 is downregulated in cystic fibrosis airway epithelial cells and regulates TOM1 expression

Role of microRNAs in the molecular diagnosis of cancer

Lung microRNA: from development to disease

Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model

Involvement of microRNAs in physiological and pathological processes in the lung

Funding was obtained from the Czech Ministry of Health (IGA MZ CR NT/ 11117-6, IGA MZ CR NS/10267-3, IGA MZ CR NS/10260-3) and in part by the Internal Grant Agency of Palacky University (IGA PU project SV LF_2010_008). The authors declare no conflicting financial interests.

All authors wrote and revised the manuscript, and approved the final version. The authors declare that they have no competing interests. 

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