title: PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma.
abstract: Glioblastoma (GBM) is a highly heterogeneous type of tumor characterized by genomic and signaling abnormalities affecting pathways involved in control of cell fate, including tumor-suppressor- and growth factor-regulated pathways. An aberrant miRNA expression has been observed in GBM, being associated with impaired cellular functions resulting in malignant transformation, proliferation and invasion. Here, we demonstrate for the first time that platelet-derived growth factor-B (PDGF-B), a potent angiogenic growth factor involved in GBM development and progression, promotes downregulation of pro-oncogenic (miR-21) and anti-oncogenic (miR-128) miRNAs, as well as upregulation/downregulation of several miRNAs involved in GBM pathology. Retrovirally mediated overexpression of PDGF-B in U87 human GBM cells or their prolonged exposure, as well as that of F98 rat glioma cells to this ligand, resulted in decreased miR-21 and miR-128 levels, which was associated with increased cell proliferation. Furthermore, siRNA-mediated PDGF-B silencing led to increased levels of miR-21 and miR-128, while miRNA modulation through overexpression of miR-21 did not alter the levels of PDGF-B. Finally, we demonstrate that modulation of tumor suppressors PTEN and p53 in U87 cells does not affect the decrease in miR-21 levels associated with PDGF-B overexpression. Overall, our findings suggest that, besides its role in inducing GBM tumorigenesis, PDGF-B may enhance tumor proliferation by modulating the expression of oncomiRs and tumor suppressor miRNAs in U87 human GBM cells.
authors.affiliation: CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004-517, Portugal.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Costa
authors.forename: Ana L
authors.initials: AL
authors.lastname: Cardoso
authors.forename: Luis F
authors.initials: LF
authors.lastname: Pereira de Almeida
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Maria C
authors.initials: MC
authors.lastname: Pedroso de Lima
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D020574:Proto-Oncogene Proteins c-sis; D016159:Tumor Suppressor Protein p53; C524940:MIRN21 microRNA, human; C525709:MIR221, human