title: MicroRNA-661 Enhances TRAIL or STS Induced Osteosarcoma Cell Apoptosis by Modulating the Expression of Cytochrome c1.
abstract: OBJECTIVE
  Osteosarcoma (OS) is an aggressive bone malignancy that affects rapidly growing bones and is associated with a poor prognosis. Our previous study showed that cytochrome c1 (CYC1), a subunit of the cytochrome bc1 complex (complex III) of the mitochondrial electron chain, is overexpressed in human OS tissues and cell lines and its silencing induces apoptosis in vitro and inhibits tumor growth in vivo. Here, we investigated the mechanism underlying the modulation of CYC1 expression in OS and its role in the resistance of OS to apoptosis.
  
  
  METHODS
  qRT-PCR, luciferase reporter assay, western blotting, fow cytometry, and animal experiments were performed in this study.
  
  
  RESULTS
  MicroRNA (miR)-661 was identified as a downregulated miRNA in OS tissues and cells and shown to directly target CYC1. Ectopically expressed miR-661 inhibited OS cell growth, promoted apoptosis, and reduced the activity of mitochondrial complex III. miR-661 overexpression enhanced TRAIL or STS induced apoptosis and promoted the release of cytochrome c into the cytosol, which induced caspase-9 activation, and these effects were abolished by a caspase-3 inhibitor. Overexpression of CYC1 rescued the effects of miR-661 on sensitizing OS cells to TRAIL or STS induced apoptosis, indicating that the antitumor effect of miR-661 is mediated by the downregulation of CYC1. In vivo, miR-661 overexpression sensitized tumors to TRAIL or STS induced apoptosis in a xenograft mouse model, and these effects were attenuated by co-expression of CYC1.
  
  
  CONCLUSIONS
  Taken together, our results indicate that miR-661 plays a tumor suppressor role in OS mediated by the downregulation of CYC1, suggesting a potential mechanism underlying cell death resistance in OS.
authors.affiliation: Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Operating Room, Shanghai Tenth People's Hospital, Shanghai, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Operating Room, Shanghai Tenth People's Hospital, Shanghai, China.
authors.forename: Rongmin
authors.initials: R
authors.lastname: Qiu
authors.affiliation: Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zan
authors.affiliation: Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Tianyang
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.|Department of Orthopedics, Shanghai Tenth People's Hospital, Nan Jing Medical University, Nangjing, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003575:Cytochromes c1 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D043266:Steryl-Sulfatase / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: C543810:MIRN661 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D003575:Cytochromes c1; C584039:STS protein, human; D043266:Steryl-Sulfatase
keywords: Cytochrome c1; MicroRNA-661; Osteosarcoma; STS; TRAIL