Abstract
Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis / physiology
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Brain Neoplasms / enzymology*
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Crizotinib
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Glioblastoma / enzymology*
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Glioblastoma / genetics
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Glioblastoma / pathology
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Humans
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Kruppel-Like Factor 4
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Mice
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras)
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism*
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STAT5 Transcription Factor / genetics*
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STAT5 Transcription Factor / metabolism
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Transfection
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ras Proteins / genetics*
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ras Proteins / metabolism
Substances
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KLF4 protein, human
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KRAS protein, human
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Klf4 protein, mouse
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Kruppel-Like Factor 4
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MIRN134 microRNA, human
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MicroRNAs
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrazoles
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Pyridines
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STAT5 Transcription Factor
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STAT5B protein, human
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Crizotinib
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Receptor Protein-Tyrosine Kinases
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Proto-Oncogene Proteins p21(ras)
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ras Proteins