Abstract
Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.
Highlights
The dual role of time, as a fearsome enemy or important ally in the course of human diseases, has motivated researchers to advance in the frantic understanding of their cellular and molecular bases, hoping to identify novel approaches for patient care
Low levels of miR-126 were found in Cystic fibrosis (CF) airway epithelial cells. This downregulation correlated with the upregulation of the target of Myb protein 1 (TOM1), which is a negative regulator of TLR2, TLR4, IL-1, IL-1β, TNF-α, and NF-kB
Every CF patient is unique with respect to her or his clinical manifestations as a result of the heterogeneity of CFTR mutations
Summary
The dual role of time, as a fearsome enemy or important ally in the course of human diseases, has motivated researchers to advance in the frantic (and necessary) understanding of their cellular and molecular bases, hoping to identify novel approaches for patient care. MicroRNAs (miRNAs), a class of small non-coding RNAs, are well known to regulate a diverse array of biological processes, such as proliferation, development, and metabolism [1,2]. Many studies showed the direct or indirect regulatory impact of deregulated miRNAs on the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) mRNA [20]. Their participation in the control of the inflammation of CF airways has been demonstrated, along with their potential role as circulating biomarkers [17]. We will summarize the therapeutic potential of miRNAs in CF
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