miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal

Maurizio Martini, Stefano Giannetti, Luigi Maria Larocca, Ruggero De Maria Marchiano, Roberto Pallini, Liliana Morgante, Alfredo Pagliuca, Valentina Lulli, Mariachiara Buccarelli, Michele Signore, Mauro Biffoni, Giovanna Marziali, Ramona Ilari, Lucia Ricci-Vitiani

Risultato della ricerca: Contributo in rivistaArticolo in rivista

33 Citazioni (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the most common and fatal malignant adult primary brain tumor. Currently, the overall prognosis for GBM patients remains poor despite advances in neurosurgery and adjuvant treatments. MicroRNAs (miRNAs) contribute to the pathogenesis of various types of tumor, including GBM. In this study we analyzed the expression of a panel of miRNAs, which are known to be differentially expressed by the brain and GBM tumor, in a collection of patient-derived GBM stem-like cells (GSCs). Notably, the average expression level of miR-135b, was the most downregulated compared to its normal counterpart, suggesting a potential role as anti-oncogene. Restoration of miR-135b in GSCs significantly decreased proliferation, migration and clonogenic abilities. More importantly, miR-135b restoration was able to significantly reduce brain infiltration in mouse models of GBM obtained by intracerebral injection of GSC lines. We identified ADAM12 and confirmed SMAD5 and GSK3β as miR-135b targets and potential mediators of its effects. The whole transcriptome analysis ascertained that the expression of miR-135b downmodulated additional genes driving key pathways in GBM survival and infiltration capabilities. Our results identify a critical role of miR-135b in the regulation of GBM development, suggesting that miR-135b might act as a tumor-suppressor factor and thus providing a potential candidate for the treatment of GBM patients.
Lingua originaleEnglish
pagine (da-a)37241-37256
Numero di pagine16
RivistaOncotarget
Volume6
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • ADAM Proteins
  • ADAM12
  • ADAM12 Protein
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cell Self Renewal
  • Down-Regulation
  • GSK3β
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genotype
  • Glioblastoma
  • Glioblastoma stem cells
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinase 3 beta
  • Heterografts
  • Humans
  • Male
  • Membrane Proteins
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells
  • Oncology
  • Phenotype
  • SMAD5
  • Signal Transduction
  • Smad5 Protein
  • Time Factors
  • Transfection
  • miRNAs

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