miR-146a, miR-155, miR-370, and miR-708 Are CFTR-Dependent, Predicted FOXO1 Regulators and Change at Onset of CFRDs.
Cystic fibrosis-related diabetes (CFRD) is the most frequent and severe co-morbidity in cystic fibrosis (CF). Presentation and severity are quite variable.



To investigate changes in microRNAs (miRNAs) due to CF transmembrane conductance regulator malfunctioning in vitro, to study the circulating levels of selected miRNAs in serum samples from patients, and to 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 CFBE41o- cells, in their normal counterparts (16HBE14o- cells), and in IB3 cells was performed. A set of miRNAs was differentially expressed in the CF cells. By in silico analysis, four miRNAs (miR-146a, miR-155, miR-370, and miR-708) were selected as potential regulators of the FOXO1 gene. Seventy-four CF patients and 50 healthy subjects whose glucose tolerance was characterized by an oral glucose tolerance test were enrolled in the study, and the identified miRNAs were quantified in serum by quantitative RT-PCR. Main Outcome Measurements/Results: A total of 111 miRNAs were differentially expressed in the two CF cell lines. miR-155, miR-370, and miR-708 were up-regulated and miR-146a was down-regulated in vitro, whereas in vivo, miR-146a, miR-155, and miR-370 were up-regulated, and miR-708 was down-regulated. These changes showed relationships with genotype, glucose tolerance state, and onset of CFRD.



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 CF.
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Luisa
L
Montanini
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Arianna
A
Smerieri
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Mariolina
M
Gullì
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Francesca
F
Cirillo
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Giovanna
G
Pisi
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Chiara
C
Sartori
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Sergio
S
Amarri
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Sergio
S
Bernasconi
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Nelson
N
Marmiroli
Department of Paediatrics (L.M., A.S., G.P., S.B.), University Hospital of Parma, 43126 Parma, Italy; Department of Life Sciences (M.G., N.M.), University of Parma, 43124 Parma, Italy; and Department of Paediatrics (F.C., C.S., S.A., M.E.S.), Arcispedale Santa Maria Nuova-IRCCS, 42123 Reggio Emilia, Italy.
Maria E
ME
Street
D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D002648:Child; D003550:Cystic Fibrosis / Q000097:blood* / Q000150:complications / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood* / Q000209:etiology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000097:blood* / Q000209:etiology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D055815:Young Adult
D015415:Biomarkers; C505032:CFTR protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C542542:MIRN146 microRNA, human; C524942:MIRN155 microRNA, human; C526503:MIRN370 microRNA, human; C568528:MIRN708 microRNA, human; D035683:MicroRNAs; D019005:Cystic Fibrosis Transmembrane Conductance Regulator