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Molecular and Cellular Biology, November 2009, p. 5923-5940, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00332-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Downregulated MicroRNA-200a in Meningiomas Promotes Tumor Growth by Reducing E-Cadherin and Activating the Wnt/β-Catenin Signaling Pathway{triangledown}

Okay Saydam,1 Yiping Shen,2 Thomas Würdinger,1,3 Ozlem Senol,1 Elvan Boke,1,{dagger} Marianne F. James,2 Bakhos A. Tannous,1 Anat O. Stemmer-Rachamimov,4 Ming Yi,5 Robert M. Stephens,5 Cornel Fraefel,6 James F. Gusella,2 Anna M. Krichevsky,7 and Xandra O. Breakefield1*

Departments of Neurology and Radiology, Massachusetts General Hospital, and Neuroscience Program, Harvard Medical School, Boston, Massachusetts 02129,1 Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114,2 Neuro-Oncology Research Group, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands,3 Molecular Neuro-Oncology Laboratory and Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129,4 Advanced Biomedical Computing Center, National Cancer Institute, Bethesda, Maryland 21702,5 Institute of Virology, University of Zurich, Zurich 8057, Switzerland,6 Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 021157

Received 15 March 2009/ Returned for modification 18 April 2009/ Accepted 13 August 2009

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 β-catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target β-catenin mRNA, thereby inhibiting its translation and blocking Wnt/β-catenin signaling, which is frequently involved in cancer. A direct correlation was found between the downregulation of miR-200a and the upregulation of β-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/β-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.

* Corresponding author. Mailing address: Molecular Neurogenetics Unit, Massachusetts General Hospital/Harvard Medical School-East, 13th Street, Building 149, Charlestown, MA 02129. Phone: (617) 726-5728. Fax: (617) 724-1537. E-mail: breakefield{at}hms.harvard.edu

{triangledown} Published ahead of print on 24 August 2009.

{dagger} Present address: Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.

Molecular and Cellular Biology, November 2009, p. 5923-5940, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00332-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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