title: The microRNA miR-17-3p inhibits mouse cardiac fibroblast senescence by targeting Par4.
abstract: The microRNA miR-17-92 cluster plays a fundamental role in heart development. The aim of this study was to investigate the effect of a member of this cluster, miR-17, on cardiac senescence. We examined the roles of miR-17 in senescence and demonstrated that miR-17-3p attenuates cardiac aging in the myocardium by targeting Par4 (also known as PAWR). This upregulates the downstream proteins CEBPB, FAK, N-cadherin, vimentin, Oct4 and Sca-1 (also known as stem cell antigen-1), and downregulates E-cadherin. Par4 has been reported as a tumor suppressor gene that induces apoptosis in cancer cells, but not in normal cells. Repression of Par4 by miR-17-3p enhances the transcription of CEBPB and FAK, which promotes mouse cardiac fibroblast (MCF) epithelial-to-mesenchymal transition (EMT) and self-renewal, resulting in cellular senescence and apoptosis resistance. We conclude that Par4 can bind to the CEBPB promoter and inhibit its transcription. Decreased Par4 expression increases the amount of CEBPB, which binds to the FAK promoter and enhances FAK transcription. Par4, CEBPB and FAK form a senescence signaling pathway, playing roles in modulating cell survival, growth, apoptosis, EMT and self-renewal. Through this novel senescence signaling axis, miR-17-3p represses Par4 expression, acting pleiotropically as a negative modulator of cardiac aging and cardiac fibroblast cellular senescence.
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: William W
authors.initials: WW
authors.lastname: Du
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada Guangdong Institute of Microbiology, Guangzhou 510070, China.
authors.forename: Xianmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: Tianbi
authors.initials: T
authors.lastname: Li
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: Haoran
authors.initials: H
authors.lastname: Li
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: Azam
authors.initials: A
authors.lastname: Khorshidi
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada.
authors.forename: Fengqiong
authors.initials: F
authors.lastname: Liu
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto ON M4N 3M5, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M4N 3M5, Canada byang@sri.utoronto.ca.
authors.forename: Burton B
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C101296:prostate apoptosis response-4 protein; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse
keywords: Senescence; miR-17; microRNA