Heparan sulfate proteoglycan modulation of Wnt5A signal transduction in metastatic melanoma cells.
Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.
O'Connell
Michael P
MP
Laboratory of Immunology, Research Resources Branch, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
Fiori
Jennifer L
JL
Kershner
Emily K
EK
Frank
Brittany P
BP
Indig
Fred E
FE
Taub
Dennis D
DD
Hoek
Keith S
KS
Weeraratna
Ashani T
AT
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D053668:Syndecan-1 / Q000378:metabolism; D053671:Syndecan-4 / Q000378:metabolism; D051153:Wnt Proteins / Q000737:chemistry* / Q000378:metabolism; D000071818:Wnt-5a Protein; D014945:Wound Healing
D019812:Heparan Sulfate Proteoglycans; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D053668:Syndecan-1; D053671:Syndecan-4; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein
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