PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma

• Published in: Human molecular genetics 2012-12, Vol.21 (23), p.5118-5130
• Main Authors: COSTA, Pedro M, CARDOSO, Ana L, PEREIRA DE ALMEIDA, Luis F, BRUCE, Jeffrey N, CANOLL, Peter, PEDROSO DE LIMA, Maria C
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Cell physiology; Disease Models, Animal; Down-Regulation - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetics of eukaryotes. Biological and molecular evolution; Glioblastoma - genetics; Glioblastoma - metabolism; Humans; Medical sciences; Mice; MicroRNAs - genetics; Molecular and cellular biology; Neurology; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - metabolism; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Rats; RNA Interference; Signal Transduction; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors of the nervous system. Phacomatoses
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/dds358

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.