title: MicroRNA-21 suppression impedes medulloblastoma cell migration.
abstract: Medulloblastoma (MB), the most common malignant brain tumour in children, is characterised by a high risk of leptomeningeal dissemination. But little is known about the molecular mechanisms that promote cancer cell migration in MB. Aberrant expression of miR-21 is recognised to be causatively linked to metastasis in a variety of human neoplasms including brain tumours; however its function in MB is still unknown. In this study we investigated the expression level and the role of miR-21 in MB cell migration. miR-21 was found to be up-regulated, compared to normal cerebellum, in 29/29 MB primary samples and 6/6 MB-derived cell lines. Inverse correlation was observed between miR-21 expression and the metastasis suppressor PDCD4, while miR-21 repression increased the release of PDCD4 protein, suggesting negative regulation of PDCD4 by miR-21 in MB cells. Anti-miR-21 decreased protein expression of the tumour cell invasion mediators MAP4K1 and JNK, which are also known to be negatively regulated by PDCD4, and down-regulated integrin protein that is essential for MB leptomeningeal dissemination. Moreover miR-21 knockdown in MB cells increased the expression of two eminent negative modulators of cancer cell migration, E-Cadherin and TIMP2 proteins that are known to be positively regulated by PDCD4. Finally and importantly, suppression of miR-21 decreased the motility of MB cells and reduced their migration across basement membranes in vitro. Together, these compelling data propose miR-21 pathway as a novel mechanism impacting MB cell dissemination and raises the possibility that curability of selected MB may be improved by pharmaceutical strategies directed towards microRNA-21.
authors.affiliation: Oncology Department, University Children's Hospital of Zurich, Switzerland.
authors.forename: Eveline
authors.initials: E
authors.lastname: Grunder
authors.forename: Rocco
authors.initials: R
authors.lastname: D'Ambrosio
authors.forename: Giulio
authors.initials: G
authors.lastname: Fiaschetti
authors.forename: Lucia
authors.initials: L
authors.lastname: Abela
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Tycho
authors.initials: T
authors.lastname: Zuzak
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
authors.forename: Sheng-Qing
authors.initials: SQ
authors.lastname: Lv
authors.forename: Tarek
authors.initials: T
authors.lastname: Shalaby
authors.forename: Michael
authors.initials: M
authors.lastname: Grotzer
mesh_terms: D000293:Adolescent; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000502:physiology*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D012334:RNA, Neoplasm / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; C114487:PDCD4 protein, human; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins