MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes.
MicroRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets, and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR-34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2, and CDK6 protein expressions in glioma cells. miR-34a expression inhibited c-Met reporter activities in glioma and medulloblastoma cells and Notch-1 and Notch-2 3'-untranslated region reporter activities in glioma cells and stem cells. Analysis of human specimens showed that miR-34a expression is down-regulated in glioblastoma tissues as compared with normal brain and in mutant p53 gliomas as compared with wild-type p53 gliomas. miR-34a levels in human gliomas inversely correlated to c-Met levels measured in the same tumors. Transient transfection of miR-34a into glioma and medulloblastoma cell lines strongly inhibited cell proliferation, cell cycle progression, cell survival, and cell invasion, but transfection of miR-34a into human astrocytes did not affect cell survival and cell cycle status. Forced expression of c-Met or Notch-1/Notch-2 transcripts lacking the 3'-untranslated region sequences partially reversed the effects of miR-34a on cell cycle arrest and cell death in glioma cells and stem cells, respectively. Also, transient expression of miR-34a in glioblastoma cells strongly inhibited in vivo glioma xenograft growth. Together, these findings represent the first comprehensive analysis of the role of miR-34a in gliomas. They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors.
Departments of Microbiology, Neurology and Pathology, University of Virginia, Charlottesville, VA 22908, USA.
Yunqing
Y
Li
Fadila
F
Guessous
Ying
Y
Zhang
Charles
C
Dipierro
Benjamin
B
Kefas
Elizabeth
E
Johnson
Lukasz
L
Marcinkiewicz
Jinmai
J
Jiang
Yanzhi
Y
Yang
Thomas D
TD
Schmittgen
Beatriz
B
Lopes
David
D
Schiff
Benjamin
B
Purow
Roger
R
Abounader
D020413:3' Untranslated Regions; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002453:Cell Cycle / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
D020413:3' Untranslated Regions; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D019859:Proto-Oncogene Proteins c-met; D020796:Receptor, Platelet-Derived Growth Factor alpha; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6