title: miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1.
abstract: As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases.
authors: EA4483, Faculté de Médecine de Lille, Pole Recherche, Lille, France.
authors: Christian Lacks
authors: CL
authors: Lino Cardenas
authors: Imène Sarah
authors: IS
authors: Henaoui
authors: Elisabeth
authors: E
authors: Courcot
authors: Christoph
authors: C
authors: Roderburg
authors: Christelle
authors: C
authors: Cauffiez
authors: Sébastien
authors: S
authors: Aubert
authors: Marie-Christine
authors: MC
authors: Copin
authors: Benoit
authors: B
authors: Wallaert
authors: François
authors: F
authors: Glowacki
authors: Edmone
authors: E
authors: Dewaeles
authors: Jadranka
authors: J
authors: Milosevic
authors: Julien
authors: J
authors: Maurizio
authors: John
authors: J
authors: Tedrow
authors: Brice
authors: B
authors: Marcet
authors: Jean-Marc
authors: JM
authors: Lo-Guidice
authors: Naftali
authors: N
authors: Kaminski
authors: Pascal
authors: P
authors: Barbry
authors: Tom
authors: T
authors: Luedde
authors: Michael
authors: M
authors: Perrais
authors: Bernard
authors: B
authors: Mari
authors: Nicolas
authors: N
authors: Pottier
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016212:Transforming Growth Factor beta / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051242:Caveolin 1; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D016212:Transforming Growth Factor beta; D001761:Bleomycin