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PMID:20208569

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Citation

Kongkham, PN, Northcott, PA, Croul, SE, Smith, CA, Taylor, MD and Rutka, JT (2010) The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma. Oncogene 29:3017-24

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.

Links

PubMed Online version:10.1038/onc.2010.32

Keywords

Adaptor Proteins, Signal Transducing/antagonists & inhibitors; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Line, Tumor; Cerebellum/metabolism; Cerebellum/pathology; DNA Methylation; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor/physiology; Glycoproteins/genetics; Glycoproteins/metabolism; Humans; Intercellular Signaling Peptides and Proteins/genetics; Intercellular Signaling Peptides and Proteins/metabolism; Medulloblastoma/genetics; Medulloblastoma/metabolism; Medulloblastoma/pathology; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Mice, Nude; Phosphoproteins/antagonists & inhibitors; Phosphoproteins/genetics; Phosphoproteins/metabolism; Phosphorylation; Promoter Regions, Genetic; Survival Rate; Wnt Proteins/metabolism; Xenograft Model Antitumor Assays

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SFRP1

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0014070: response to organic cyclic compound

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP2

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP2

involved_in

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP2

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP3

involved_in

GO:0008285: negative regulation of cell population proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP3

involved_in

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP3

involved_in

GO:0030308: negative regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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