title: MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts.
abstract: MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (IPF). Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix (ECM), in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex leading to extrinsic apoptosis. The representative profibrotic transforming growth factor (TGF)-β downregulated the expression of miR-29c as well as Fas receptor and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-β-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF.
authors.affiliation: Pharmacology Research Laboratories, Watarase Research Center, Kyorin Pharmaceutical Co., Shimotsuga-gun, Tochigi, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsushima
authors.affiliation: Pharmacology Research Laboratories, Watarase Research Center, Kyorin Pharmaceutical Co., Shimotsuga-gun, Tochigi, Japan junichi.ishiyama@mb.kyorin-pharm.co.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Ishiyama
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D044127:Epigenesis, Genetic / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology*; D008297:Male; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C491901:FAS protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D016212:Transforming Growth Factor beta; D019014:fas Receptor
keywords: Fas; TGF-β; apoptosis resistance; fibrosis; miR-29