**1. Introduction**

Cystic Fibrosis (CF) is due to mutations in the CF transmembrane conductance regulator (CFTR) gene causing impairment of chloride ions exchanges through the apical membrane of epithelial cells. CF affects epithelia in a variety of organs, notably lung, intestine, pancreas and the reproductive system. The most common CFTR mutation, F508del, results in deletion of a

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phenylalanine at position 508 of the protein, and the mutated protein is retained in the endoplasmic reticulum and rapidly degraded via the endoplasmic reticulum-associated degradation pathway. Up to now, almost 2000 CFTR mutations have been identified (http:// genet.sickkids.on.ca). A good correlation can generally be observed between *CFTR* genotype and the gastrointestinal disease, the pancreatic status, and the reproductive tract abnormali‐ ties, but the lung disease outcome is difficult to predict based solely on *CFTR* genotype (http:// www.cftr2.org/). For example, it has been shown that siblings and monozygous twins, thus carrying the same *CFTR* genotype, even if living in the same environment and receiving the same medical care, may develop different spatial and temporal patterns in lung disease progression. The basis for variability in severity of CF lung disease is poorly understood and depends on concomitant expression of other genetic and environmental factors. Over the recent years, exploring the role of genetics/genomics (e.g. modifier genes, gene-environment interactions, epigenetics, etc.) has received growing attention in CF, with the aim of unveiling basic mechanisms and bringing in better understanding of the pathophysiology of the disease, helping to predict its progression, and hopefully leading to specially designed novel thera‐ peutic strategies.

Of the whole human genome, only a small fraction, the protein-coding part, has long attracted attention because of the pervasive role of genes in determining amino acid sequences of expressed proteins, leading to observable consequences of mutations. Later on, following the discovery of transduction factors regulating gene translation, the initial view of "junk DNA", corresponding to the majority of DNA, had to be revisited. Following the identification of nonmessenger RNA functions, the new concept of a network of non-coding transcriptome that regulates protein-coding expression emerged.

Non-coding RNAs are presently broadly categorized into three classes. The major class (well over 90% of total RNA) makes up the so-called housekeeping RNAs; they consist of small nuclear, small nucleolar, transfer, and ribosomal RNAs, the latter interacting with protein and transfer RNA to form the functional ribosome complex. The other classes of non-coding RNAs are long (>200) and short (<200) ribonucleotides. The best characterized and most extensively studied family of non-coding RNAs is that of microRNAs (miRNAs), short (17--27 nucleotides in length) single-stranded RNA molecules, which negatively regulate the translation of messenger RNAs into proteins. Figure 1 summarizes the general mechanism of biogenesis of miRNAs. Highly phylogenetically conserved, they bind to the 3'UTR (untranslated region) of target mRNAs, thereby potently repressing the target mRNA translation into protein or favoring mRNA degradation. To date, more than 1800 mature miRNAs have been identified in the human genome (http://www.mirbase.org). Bioinformatics studies predict that miRNAs potentially regulate the expression of about 60% of human genes.

As essential components of the regulatory system of gene expression, miRNAs have been shown to influence the development, the severity, the prognosis and/or the progression of a number of inherited diseases [1]. Differential expression studies of miRNAs have evidenced an impact on lung disease development in chronic obstructive pulmonary disease (COPD), asthma, lung inflammation, consequences of smoke exposure and airway allergy in human and in animal models of the diseases [2]. Since marked inflammation is a major feature of CF

**Figure 1.** Biogenesis of microRNAs (miRNAs). miRNA genes are transcribed by RNA-polymerase 2 into primary mi-RNA (pri-miRNA) precursors. The pri-miRNAs are cleaved in the nucleus by a nuclear protein complex including the class 2 ribonuclease III Drosha to produce pre-miRNAs. Pre-miRNAs are exported to the cytoplasm via the nuclear export protein Exportin. In the cytoplasm, a pre-miRNA is cleaved by a protein complex including the helicase Dicer and form a duplex of miRNAs containing the mature miRNA bound to its complementary sequence (miRNA\*). Du‐ plexes are unwound and mature miRNAs bind to the 3'UTR of the target mRNA within the RNA-induced silencing complex to prevent translation by inhibition of ribosomes binding or mRNA degradation.

lung disease, miRNAs may be expected to play a role in its pathogenesis. Indeed, recent clinical and cell-based studies have revealed CF-specific alterations in miRNA expression. This point will be extensively discussed further below.

In this article, we review and highlight some of the most relevant published data focusing on miRNAs in CF. The first section deals with regulation of CFTR expression and modulation of CFTR trafficking. In the second section, key elements of inflammatory and innate immune responses in with CF airways are reviewed, focusing on the potential role of miRNAs in molecular pathways involved in lung inflammation. The third section discusses the potential role of miRNAs in lung development, differentiation and remodeling. The next section explores strategies to exploit miRNAs as biomarkers and potential therapies of CF disease. Finally, limitations in translating miRNAs from deeper knowledge of their role in pathogenesis to development of new therapies are highlighted.
