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The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma

Oncogene volume 29, pages 3017–3024 (2010)Cite this article

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Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Dysregulation of WNT signaling occurs in up to 20% of cases. Using a genome-wide approach, we identified the secreted frizzled-related protein 1, 2 and 3 (SFRP1, SFRP2 and SFRP3) family of WNT inhibitors as putative tumor suppressor genes silenced by promoter region methylation in MB. SFRP1, SFRP2 and SFRP3 expression increased after 5-aza-2′-deoxycytidine treatment. SFRP1, SFRP2 and SFRP3 methylation was identified in 23.5, 3.9 and 15.7% of primary MB specimens, respectively, by methylation-specific PCR. Stable SFRP1, SFRP2 and SFRP3 expression reduced phospho-DVL2 levels and hindered MB cell proliferation and colony formation in soft agar in vitro. In 60% of primary tumors, SFRP1 was expressed at levels twofold lower than that in normal cerebellum. SFRP1 expression impaired tumor formation in vivo in flank and orthotopic intracerebellar xenograft models and conferred a significant survival advantage (P<0.0001). We identify for the first time tumor suppressor gene function of SFRP genes in MB, and suggest that loss of WNT pathway inhibition due to SFRP gene silencing is an additional mechanism that may contribute to excessive WNT signaling in this disease.

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Acknowledgements

This work was supported by grants from the Canadian Cancer Society, National Cancer Institute of Canada (019073), the Pediatric Brain Tumor Foundation, the Wiley Fund at the Hospital for Sick Children and B.r.a.i.n.child. James Rutka is a scientist of the Canadian Institutes of Health Research. Paul Kongkham was supported by the Surgeon Scientist Program (University of Toronto), the National Cancer Institute of Canada Terry Fox Foundation clinical research fellowship and a research studentship from RESTRACOMP, The Hospital for Sick Children, Toronto.

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Authors and Affiliations

  1. Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, Ontario, Canada

    P N Kongkham, P A Northcott, C A Smith, M D Taylor & J T Rutka

  2. Program in Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    P N Kongkham, C A Smith & J T Rutka

  3. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    P A Northcott & M D Taylor

  4. Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada

    S E Croul

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  1. P N Kongkham
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Correspondence to J T Rutka.

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Kongkham, P., Northcott, P., Croul, S. et al. The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma. Oncogene 29, 3017–3024 (2010). https://doi.org/10.1038/onc.2010.32

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  • DOI: https://doi.org/10.1038/onc.2010.32

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