title: MicroRNA-21 promotes glioblastoma tumorigenesis by down-regulating insulin-like growth factor-binding protein-3 (IGFBP3).
abstract: Despite advances in surgery, imaging, chemotherapy, and radiation, patients with glioblastoma multiforme (GBM), the most common histological subtype of glioma, have an especially dismal prognosis; >70% of GBM patients die within 2 years of diagnosis. In many human cancers, the microRNA miR-21 is overexpressed, and accumulating evidence indicates that it functions as an oncogene. Here, we report that miR-21 is overexpressed in human GBM cell lines and tumor tissue. Moreover, miR-21 expression in GBM patient samples is inversely correlated with patient survival. Knockdown of miR-21 in GBM cells inhibited cell proliferation in vitro and markedly inhibited tumor formation in vivo. A number of known miR-21 targets have been identified previously. By microarray analysis, we identified and validated insulin-like growth factor (IGF)-binding protein-3 (IGFBP3) as a novel miR-21 target gene. Overexpression of IGFBP3 in glioma cells inhibited cell proliferation in vitro and inhibited tumor formation of glioma xenografts in vivo. The critical role that IGFBP3 plays in miR-21-mediated actions was demonstrated by a rescue experiment, in which IGFBP3 knockdown in miR-21KD glioblastoma cells restored tumorigenesis. Examination of tumors from GBM patients showed that there was an inverse relationship between IGFBP3 and miR-21 expression and that increased IGFBP3 expression correlated with better patient survival. Our results identify IGFBP3 as a novel miR-21 target gene in glioblastoma and suggest that the oncogenic miRNA miR-21 down-regulates the expression of IGFBP3, which acts as a tumor suppressor in human glioblastoma.
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Chuan He
authors: CH
authors: Yang
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Junming
authors: J
authors: Yue
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Susan R
authors: SR
authors: Pfeffer
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Meiyun
authors: M
authors: Fan
authors: Surgery.
authors: Elena
authors: E
authors: Paulus
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Amira
authors: A
authors: Hosni-Ahmed
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Michelle
authors: M
authors: Sims
authors: From the Departments of Pathology and Laboratory Medicine and.
authors: Sohail
authors: S
authors: Qayyum
authors: From the Departments of Pathology and Laboratory Medicine and Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38103.
authors: Andrew M
authors: AM
authors: Davidoff
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and.
authors: Charles R
authors: CR
authors: Handorf
authors: From the Departments of Pathology and Laboratory Medicine and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163 and Lpfeffer@uthsc.edu.
authors: Lawrence M
authors: LM
authors: Pfeffer
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C515497:IGFBP3 protein, human; C507942:Il2rg protein, mouse; D018972:Insulin-Like Growth Factor Binding Protein 3; D053631:Interleukin Receptor Common gamma Subunit; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D008156:Luciferases
keywords: Brain Tumor; Glioblastoma; IGFBP3; Insulin-like Growth Factor (IGF); MicroRNA (MiRNA); Tumor Suppressor Gene