title: Two mature products of MIR-491 coordinate to suppress key cancer hallmarks in glioblastoma.
abstract: MIR-491 is commonly co-deleted with its adjacent CDKN2A on chromosome 9p21.3 in glioblastoma multiforme (GBM). However, it is not known whether deletion of MIR-491 is only a passenger event or has an important role. Small-RNA sequencing of samples from GBM patients demonstrated that both mature products of MIR-491 (miR-491-5p and -3p) are downregulated in tumors compared with the normal brain. The integration of GBM data from The Cancer Genome Atlas (TCGA), miRNA target prediction and reporter assays showed that miR-491-5p directly targets EGFR, CDK6 and Bcl-xL, whereas miR-491-3p targets IGFBP2 and CDK6. Functionally, miR-491-3p inhibited glioma cell invasion; overexpression of both miR-491-5p and -3p inhibited proliferation of glioma cell lines and impaired the propagation of glioma stem cells (GSCs), thereby prolonging survival of xenograft mice. Moreover, knockdown of miR-491-5p in primary Ink4a-Arf-null mouse glial progenitor cells exacerbated cell proliferation and invasion. Therefore, MIR-491 is a tumor suppressor gene that, by utilizing both mature forms, coordinately controls the key cancer hallmarks: proliferation, invasion and stem cell propagation.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yuexin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland.
authors.forename: Kirsi J
authors.initials: KJ
authors.lastname: Granberg
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an, China.
authors.forename: Qinhao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Moore
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.affiliation: Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Non-coding RNA center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: Department of Pathology, Fimlab Laboratories and University of Tampere, Tampere, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.affiliation: Department of Signal Processing, Tampere University of Technology, Tampere, Finland.|Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Institute for Systems Biology, Seattle, Washington, USA.
authors.forename: Ilya
authors.initials: I
authors.lastname: Shmulevich
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Non-coding RNA center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000032:analysis; D066246:ErbB Receptors / Q000032:analysis; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000032:analysis; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D009361:Neoplasm Invasiveness; D051020:bcl-X Protein / Q000032:analysis
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; C551410:MIRN491 microRNA, human; D035683:MicroRNAs; D051020:bcl-X Protein; D066246:ErbB Receptors; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6
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