title: Differentially expressed miRNAs in Ewing sarcoma compared to mesenchymal stem cells: low miR-31 expression with effects on proliferation and invasion.
abstract: Ewing sarcoma, the second most common bone tumor in children and young adults, is an aggressive malignancy with a strong potential to metastasize. Ewing sarcoma is characterised by translocations encoding fusion transcription factors with an EWSR1 transactivation domain fused to an ETS family DNA binding domain. microRNAs are post-transcriptional regulators of gene expression and aberrantly expressed microRNAs have been identified as tumor suppressors or oncogenes in most cancer types. To identify potential oncogenic and tumor suppressor microRNAs in Ewing sarcoma, we determined and compared the expression of 377 microRNAs in 40 Ewing sarcoma biopsies, 6 Ewing sarcoma cell lines and mesenchymal stem cells, the putative cellular origin of Ewing sarcoma, from 6 healthy donors. Of the 35 differentially expressed microRNAs identified (fold change >4 and q<0.05), 19 were higher and 16 lower expressed in Ewing sarcoma. In comparisons between Ewing sarcoma samples with EWS-FLI or EWS-ERG translocations, with differing dissemination characteristics and of primary samples and metastases no significantly differential expressed microRNAs were detected using various stringency criteria. For miR-31, the microRNA with lowest expression in comparison to mesenchymal stem cells, functional analyses were performed to determine its potential as a tumor suppressor in Ewing sarcoma. Two of four miR-31 transfected Ewing sarcoma cell lines showed a significantly reduced proliferation (19% and 33% reduction) due to increased apoptosis in one and increased length of G1-phase in the other cell line. All three tested miR-31 transfected Ewing sarcoma cell lines showed significantly reduced invasiveness (56% to 71% reduction). In summary, we identified 35 microRNAs differentially expressed in Ewing sarcoma and demonstrate that miR-31 affects proliferation and invasion of Ewing sarcoma cell lines in ex vivo assays.
authors.affiliation: Gerhard-Domagk-Institute for Pathology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Karnuth
authors.affiliation: Department of Orthopedics and Tumor Orthopedics, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dedy
authors.affiliation: Gerhard-Domagk-Institute for Pathology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Spieker
authors.affiliation: Departments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Lawlor
authors.affiliation: Department of Pathology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.affiliation: Pediatric Hematology and Oncology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ranft
authors.affiliation: Pediatric Hematology and Oncology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Dirksen
authors.affiliation: Pediatric Hematology and Oncology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Jürgens
authors.affiliation: Gerhard-Domagk-Institute for Pathology, University Hospital Münster, Westfälische Wilhelms-University, Münster, Germany; Department of Pathology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bräuninger
mesh_terms: D000328:Adult; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D012512:Sarcoma, Ewing / Q000235:genetics* / Q000473:pathology*
chemical_list: C534612:MIRN31 microRNA, human; D035683:MicroRNAs