title: Restoration of miR-127-3p and miR-376a-3p counteracts the neoplastic phenotype of giant cell tumor of bone derived stromal cells by targeting COA1, GLE1 and PDIA6.
abstract: Although generally benign, giant cell tumors of bone (GCTB) display an aggressive behavior associated with significant bone destruction and lung metastasis in rare cases. This and the very high recurrence rate observed after surgical resection ranging from 20 to 55% necessitates the development of more effective treatment strategies. To identify valuable therapeutic targets, we screened a previously identified microRNA signature consisting of 23 microRNAs predominantly down-regulated in GCTB. We preselected eight candidate microRNAs and analyzed the impact of their restored expression on the neoplastic phenotype of GCTB stromal cells (GCTSC). A consistent and significant inhibition of cell proliferation, migration, colony formation and spheroid formation could be induced by transfection of primary GCTSC cell lines with miR-127-3p and miR-376a-3p, respectively. Genome wide expression analysis of miR-127-3p and miR-376a-3p transfected cells revealed four novel target genes for each microRNA. Luciferase reporter assays demonstrated direct interactions of miR-127-3p with COA1 and direct interaction of miR-376a-3p with GLE1 and PDIA6, suggesting a pivotal role of these genes in the molecular etiology of GTCB. Interestingly, both microRNAs are located within a chromosomal region frequently silenced in GCTB and many other types of cancers, indicating that these microRNAs and their target genes are valuable therapeutic targets for the treatment of GCTB and possibly other tumor entities.
authors.affiliation: Clinic for Orthopedics and Trauma Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: joerg.fellenberg@med.uni-heidelberg.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Fellenberg
authors.affiliation: Clinic for Orthopedics and Trauma Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Sähr
authors.affiliation: Clinic for Orthopedics and Trauma Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Pierre
authors.initials: P
authors.lastname: Kunz
authors.affiliation: Surgical Research, General Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Surgical Research, General Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: German Cancer Research Center, Division of Biostatistics, Heidelberg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Tichy
authors.affiliation: Surgical Research, General Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Herr
mesh_terms: D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D018212:Giant Cell Tumor of Bone / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular; D017154:Stromal Cells / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C474082:Gle1 protein, human; C547276:MIRN127 microRNA, human; C573498:MIRN376C microRNA, human; D035683:MicroRNAs; D029543:Nucleocytoplasmic Transport Proteins; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases
keywords: Giant cell tumor of bone; Mesenchymal stem cell; MiR-127-3p; MiR-376a-3p; MicroRNA; Neoplastic transformation