title: miR-135b suppresses tumorigenesis in glioblastoma stem-like cells impairing proliferation, migration and self-renewal.
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.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lulli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mariachiara
authors.initials: M
authors.lastname: Buccarelli
authors.affiliation: Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Martini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Signore
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Institute of Human Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Giannetti
authors.affiliation: Institute of Human Anatomy, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Liliana
authors.initials: L
authors.lastname: Morgante
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marziali
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Ramona
authors.initials: R
authors.lastname: Ilari
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pagliuca
authors.affiliation: Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Luigi Maria
authors.initials: LM
authors.lastname: Larocca
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Institute of Neurosurgery, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pallini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ricci-Vitiani
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072199:ADAM12 Protein; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010641:Phenotype; D015398:Signal Transduction; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C544965:MIRN135 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D051902:Smad5 Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human
keywords: ADAM12; GSK3β; SMAD5; glioblastoma stem cells; miRNAs