Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma.
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.
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Y
Y
Zhang
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
J
J
Kim
Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
A C
AC
Mueller
Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
B
B
Dey
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
Y
Y
Yang
Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA.
D-h
DH
Lee
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
J
J
Hachmann
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
S
S
Finderle
Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA.
D M
DM
Park
Pfizer Global Research and Development, La Jolla, CA, USA.
J
J
Christensen
Department of Neurology, University of Virginia, Charlottesville, VA, USA.
D
D
Schiff
Department of Neurology, University of Virginia, Charlottesville, VA, USA.
B
B
Purow
Department of Biochemistry, University of Virginia, Charlottesville, VA, USA.
A
A
Dutta
1] Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA [2] Cancer Center, University of Virginia, Charlottesville, VA, USA.
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Abounader
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
C000715467:KLF4 protein, human; C117307:KRAS protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C569273:MIRN134 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D050799:STAT5 Transcription Factor; C494095:STAT5B protein, human; D000077547:Crizotinib; D020794:Receptor Protein-Tyrosine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins