title: Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma.
abstract: BACKGROUND
  microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated.
  
  
  METHODS
  Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells.
  
  
  RESULTS
  microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation.
  
  
  CONCLUSIONS
  microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma.
authors.affiliation: Neuro-Oncology group, Experimental Infectious Diseases and Cancer Research, August-Forel Strasse 1, Zurich CH-8008, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Fiaschetti
authors.affiliation: Division of Oncology, University Children's Hospital of Zürich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Abela
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Section of Molecular Pathology, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France.
authors.forename: N
authors.initials: N
authors.lastname: Nonoguchi
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, MaRS Centre - 11-401M, 101 College Street, Toronto, ON M5G1L7, Canada.
authors.forename: A M
authors.initials: AM
authors.lastname: Dubuc
authors.affiliation: Brain Tumor Research Centre, 101 College Street, TMDT-11-401M, Toronto, ON M5G1L7, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Remke
authors.affiliation: Oncology group, Experimental Infectious Diseases and Cancer Research, August-Forel Strasse 1, Zurich CH-8008, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Boro
authors.affiliation: Division of Oncology, University Children's Hospital of Zürich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Grunder
authors.affiliation: Division of Immunology, University Children's Hospital of Zürich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Siler
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Section of Molecular Pathology, 150 Cours Albert Thomas, 69372, Lyon Cedex 08, France.
authors.forename: H
authors.initials: H
authors.lastname: Ohgaki
authors.affiliation: The Hospital for Sick Children, Division of Neurosurgery, Suite 1504, 555 University Avenue, Toronto, ON M5G1X8, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: Neuro-Oncology group, Experimental Infectious Diseases and Cancer Research, August-Forel Strasse 1, Zurich CH-8008, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Baumgartner
authors.affiliation: Neuro-Oncology group, Experimental Infectious Diseases and Cancer Research, August-Forel Strasse 1, Zurich CH-8008, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Shalaby
authors.affiliation: Division of Oncology, University Children's Hospital of Zürich, Steinwiesstrasse 75, Zurich CH-8032, Switzerland.
authors.forename: M A
authors.initials: MA
authors.lastname: Grotzer
mesh_terms: D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002531:Cerebellum / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D005333:Fetus / Q000378:metabolism; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human