title: miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis.
abstract: Pathologic features of idiopathic pulmonary fibrosis (IPF) include genetic predisposition, activation of the unfolded protein response, telomere attrition, and cellular senescence. The mechanisms leading to alveolar epithelial cell (AEC) senescence are poorly understood. MicroRNAs (miRNAs) have been reported as regulators of cellular senescence. Senescence markers including p16, p21, p53, and senescence-associated β-galactosidase (SA-βgal) activity were measured in type II AECs from IPF lungs and unused donor lungs. miRNAs were quantified in type II AECs using gene expression arrays and quantitative RT-PCR. Molecular markers of senescence (p16, p21, and p53) were elevated in IPF type II AECs. SA-βgal activity was detected in a greater percentage in type II AECs isolated from IPF patients (23.1%) compared to patients with other interstitial lung diseases (1.2%) or normal controls (0.8%). The relative levels of senescence-associated miRNAs miR-34a, miR-34b, and miR-34c, but not miR-20a, miR-29c, or miR-let-7f were significantly higher in type II AECs from IPF patients. Overexpression of miR-34a, miR-34b, or miR-34c in lung epithelial cells was associated with higher SA-βgal activity (27.8%, 35.1%, and 38.2%, respectively) relative to control treated cells (8.8%). Targets of miR-34 miRNAs, including E2F1, c-Myc, and cyclin E2, were lower in IPF type II AECs. These results show that markers of senescence are uniquely elevated in IPF type II AECs and suggest that the miR-34 family of miRNAs regulate senescence in IPF type II AECs.
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Supparerk
authors.initials: S
authors.lastname: Disayabutr
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.|Department of Internal Medicine, CHA Bundang Medical Center, College of Medicine, CHA University, Seongnam, Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.|Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.
authors.forename: Seung-Ick
authors.initials: SI
authors.lastname: Cha
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Green
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Ram P
authors.initials: RP
authors.lastname: Naikawadi
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Golden
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
authors.affiliation: Department of Surgery, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jasleen
authors.initials: J
authors.lastname: Kukreja
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
mesh_terms: D000072283:A549 Cells; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D016922:Cellular Senescence / Q000235:genetics*; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000502:physiology*; D046228:Microarray Analysis
chemical_list: D015415:Biomarkers; C522425:MIRN34 microRNA, human; D035683:MicroRNAs