miR-146a, miR-155, miR-370 and miR-708 are CFTRdependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs

Context: Cystic Fibrosis Related Diabetes (CFRD) is the most frequent and severe co-morbidity in CF. Presentation and severity are quite variable. Objective: To investigate changes in miRNAs due to CFTR malfunctioning in vitro and to study the circulating levels of selected miRNAs in serum samples from patients, and assess their relationships in different age-groups with genotype, glucose tolerance state and at onset of CFRD. Design/Setting/Patients/Interventions: Transcriptional profiling of all known miRNAs in CFBE41ocells, in their normal counterparts (16HBE14o- cells),andin IB3 cellswasperformed.Aset ofmiRNAs was differentially expressed in the CF cells. By in silico analysis four microRNAs (miR-146a; miR-155; miR-370; miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and fifty healthy subjects whose glucose tolerance was characterized by an OGTT were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements /Results: 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, miR-708 were upregulated and miR-146a downregulated in vitro, whereas in vivo, miR-146a, miR-155 and miR-370 were upregulated, and miR-708 was downregulated. These changes showed relationships with genotype, glucose tolerance state and onset of CFRD. Conclusions: The data showed significant changes in miRNAs dependent on genotype and glucose tolerance state in CF patients, and highlighted some miRNAs of importance in CFRD at onset. MiRNAs could explain some of the variability observed in cystic fibrosis.