Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway.
Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, are usually benign, and are frequently associated with neurofibromatosis type 2. Here, we define a typical human meningioma microRNA (miRNA) profile and characterize the effects of one downregulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Upregulation of miR-200a decreased the expression of transcription factors ZEB1 and SIP1, with consequent increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Downregulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of beta-catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target beta-catenin mRNA, thereby inhibiting its translation and blocking Wnt/beta-catenin signaling, which is frequently involved in cancer. A direct correlation was found between the downregulation of miR-200a and the upregulation of beta-catenin in human meningioma samples. Thus, miR-200a appears to act as a multifunctional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and Wnt/beta-catenin signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas.
Saydam
Okay
O
Department of Neurology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts 02129, USA.
Shen
Yiping
Y
Würdinger
Thomas
T
Senol
Ozlem
O
Boke
Elvan
E
James
Marianne F
MF
Tannous
Bakhos A
BA
Stemmer-Rachamimov
Anat O
AO
Yi
Ming
M
Stephens
Robert M
RM
Fraefel
Cornel
C
Gusella
James F
JF
Krichevsky
Anna M
AM
Breakefield
Xandra O
XO
D017209:Apoptosis; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism*; D049109:Cell Proliferation; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008577:Meningeal Neoplasms / Q000235:genetics* / Q000473:pathology; D008579:Meningioma / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1
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