Heparan Sulfate Proteoglycan Modulation of Wnt5A Signal Transduction in Metastatic Melanoma Cells

Abstract

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. 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. The American Cancer Society estimates that in 2009 there will be 68,720 new cases of melanoma in this country with ∼8,650 deaths. Recent studies have demonstrated that the non-canonical Wnt pathway, also known as the Wnt/Ca2+ pathway, plays an important role in increasing the metastatic potential of melanoma cells (1Weeraratna A.T. Jiang Y. Hostetter G. Rosenblatt K. Duray P. Bittner M. Trent J.M. Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 3Dissanayake S.K. Olkhanud P.B. O'Connell M.P. Carter A. French A.D. Camilli T.C. Emeche C.D. Hewitt K.J. Rosenthal D.T. Leotlela P.D. Wade M.S. Yang S.W. Brant L. Nickoloff B.J. Messina J.L. Biragyn A. Hoek K.S. Taub D.D. Longo D.L. Sondak V.K. Hewitt S.M. Weeraratna A.T. Cancer Res. 2008; 68: 10205-10214Crossref PubMed Scopus (102) Google Scholar, 4Da Forno P.D. Pringle J.H. Hutchinson P. Osborn J. Huang Q. Potter L. Hancox R.A. Fletcher A. Saldanha G.S. Clin. Cancer Res. 2008; 14: 5825-5832Crossref PubMed Scopus (136) Google Scholar, 5O'Connell M.P. Fiori J.L. Baugher K.M. Indig F.E. French A.D. Camilli T.C. Frank B.P. Earley R. Hoek K.S. Hasskamp J.H. Elias E.G. Taub D.D. Bernier M. Weeraratna A.T. J. Invest. Dermatol. 2009; 129: 1782-1789Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). Studies from our laboratory demonstrated that increasing Wnt5A, which mediates the non-canonical Wnt/Ca2+ signaling pathway, increased melanoma metastasis (1Weeraratna A.T. Jiang Y. Hostetter G. Rosenblatt K. Duray P. Bittner M. Trent J.M. Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 3Dissanayake S.K. Olkhanud P.B. O'Connell M.P. Carter A. French A.D. Camilli T.C. Emeche C.D. Hewitt K.J. Rosenthal D.T. Leotlela P.D. Wade M.S. Yang S.W. Brant L. Nickoloff B.J. Messina J.L. Biragyn A. Hoek K.S. Taub D.D. Longo D.L. Sondak V.K. Hewitt S.M. Weeraratna A.T. Cancer Res. 2008; 68: 10205-10214Crossref PubMed Scopus (102) Google Scholar), and silencing Wnt5A levels via siRNA 3The abbreviations used are: siRNAsmall interfering RNAPKCprotein kinase CHSPGheparan sulfate proteoglycanGAGglycosaminoglycanPBSphosphate-buffered salineDMB1,9-dimethylmethylene blue. decreased invasion (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 3Dissanayake S.K. Olkhanud P.B. O'Connell M.P. Carter A. French A.D. Camilli T.C. Emeche C.D. Hewitt K.J. Rosenthal D.T. Leotlela P.D. Wade M.S. Yang S.W. Brant L. Nickoloff B.J. Messina J.L. Biragyn A. Hoek K.S. Taub D.D. Longo D.L. Sondak V.K. Hewitt S.M. Weeraratna A.T. Cancer Res. 2008; 68: 10205-10214Crossref PubMed Scopus (102) Google Scholar). In addition, we have shown that Wnt5A acts via protein kinase C (PKC) to mediate the motility of melanoma cells via the inhibition of metastasis suppressors and an initiation of the epithelial to mesenchymal transition, characterized by the loss of E-cadherin and the up-regulation of Snail (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). small interfering RNA protein kinase C heparan sulfate proteoglycan glycosaminoglycan phosphate-buffered saline 1,9-dimethylmethylene blue. Wnt signaling can be mediated by heparan sulfate proteoglycans (HSPGs) which are important signal transduction modulators. They mediate fibroblast growth factor, Hedgehog, epidermal growth factor, transforming growth factor-β, and WNT signaling pathways (6Lamanna W.C. Frese M.A. Balleininger M. Dierks T. J. Biol. Chem. 2008; 283: 27724-27735Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 7Yan D. Lin X. Nat. Cell Biol. 2008; 10: 761-763Crossref PubMed Scopus (18) Google Scholar, 8Mahtouk K. Cremer F.W. Rème T. Jourdan M. Baudard M. Moreaux J. Requirand G. Fiol G. De Vos J. Moos M. Quittet P. Goldschmidt H. Rossi J.F. Hose D. Klein B. Oncogene. 2006; 25: 7180-7191Crossref PubMed Scopus (73) Google Scholar, 9Muñoz R. Moreno M. Oliva C. Orbenes C. Larraín J. Nat. Cell Biol. 2006; 8: 492-500Crossref PubMed Scopus (118) Google Scholar, 10Hiraga T. Nakajima T. Ozawa H. Bone. 1995; 16: 349-356Crossref PubMed Scopus (59) Google Scholar, 11Filmus J. Capurro M. Rast J. Genome Biol. 2008; 9: 224Crossref PubMed Scopus (437) Google Scholar). 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Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). These two with the that Wnt5A S.K. Weeraratna A.T. Biol. 2008; PubMed Scopus Google Scholar), to that HSPGs be in increasing the of Wnt5A to in an increase in autocrine signaling and an increase in cellular In this we this and the role of HSPGs in the Wnt5A signaling in metastatic melanoma cells. cells in and and in with and and 4 Cell in and the Cell metastatic potential and Wnt5A levels, as (1Weeraratna A.T. Jiang Y. Hostetter G. Rosenblatt K. Duray P. Bittner M. Trent J.M. Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). in and to with and and for and to a a The a to and used to protein The to protein levels, with a protein as a to the levels of GAG chains the cell 1 cells in or the cells in to of and a the cells in protein and levels with protein and and and in for in and and for 1 used as syndecan syndecan syndecan and syndecan 4 in and cells 4 in and with the or for 1 in and a for 1 and with in for and to for and the of cells with or for a further and cell in and to Cell as (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). of protein a and to the the in saline in for 1 with in and 4 with used Wnt5A Cell and Cell in and the in for 1 with The in and 1 a and two and of the or a a of 1 the the cells for and with for and a as for and with for or for in the in the of a in the of the for The and the invasion a cell and for The in and the the cells and from the of the The to and in for of the to a for and the and siRNA cells for as (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). The used which have to with as as from the These are with of the the the which to the and the of caused by the siRNA are as RNA and an as (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). RNA an and 1 of an and expression the of in with a of to the an the the in a new a cell surface protein the cells in to and and and for The of to by Cell a the with the of the and and for in a for to the from the to and with the levels a protein and of protein a as and and of and to in as We have the melanoma cells used in this as Wnt5A levels and metastatic (2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). We used to the of sulfate GAG metastatic cells sulfate which indicate in HSPG core levels, synthesis, or GAG levels increase in metastatic we also a increased in metastatic cells as with metastatic cells HSPGs could downstream Wnt5A signaling, to the HSPG Following cells with an sulfate that a by and by cells with demonstrate by also used to from cells in to GAG chains could be in the increased levels of HSPG GAG chains can be in the as with the The metastatic cells have of GAG increased levels of Wnt5A can also be in the in the Wnt5A in the which have Wnt5A increase of Wnt5A in the of two HSPGs Wnt5A the surface of the in to for autocrine signaling, and HSPG Wnt5A the or HSPGs be increases Wnt5A and which of the cells with protein and We have demonstrated that Wnt5A signaling increases as as cell motility S.K. Olkhanud P.B. O'Connell M.P. Carter A. French A.D. Camilli T.C. Emeche C.D. Hewitt K.J. Rosenthal D.T. Leotlela P.D. Wade M.S. Yang S.W. Brant L. Nickoloff B.J. Messina J.L. Biragyn A. Hoek K.S. Taub D.D. Longo D.L. Sondak V.K. Hewitt S.M. Weeraratna A.T. Cancer Res. 2008; 68: 10205-10214Crossref PubMed Scopus (102) Google Scholar). HSPGs the and of Wnt5A, increasing signaling, Wnt5A from the in a decreased of Wnt5A to signal and mediate HSPG in increased of Wnt5A and the to the of a factor, we increased levels of cellular Wnt5A and increased levels of increase with and in decreased by and Wnt5A levels also that the increased levels of Wnt5A in the to increased of Wnt5A could be by cellular levels of Wnt5A decreased with a decrease in in the of we have Wnt signaling in melanoma M. J. A. B. T. A. D. and A. T. in data indicate that in the of Wnt5A signaling be decreased to the of a further that Wnt5A with cells with which be to for with Wnt5A, in in the in the of secreted Wnt5A in the of metastatic melanoma cells The of recombinant Wnt5A to metastatic cells resulted in secreted the in the of in the as by the of the and Wnt5A signaling also decreased this could be by the of the of cells with as shown decreased signaling, the cell with could signaling to indicate that increases the of Wnt to and signaling, in the of an of there that be that the cells used in this have levels of in or signaling or further that Wnt5A signaling increased we since we have demonstrated that Wnt5A signaling increases of melanoma cells (1Weeraratna A.T. Jiang Y. Hostetter G. Rosenblatt K. Duray P. Bittner M. Trent J.M. Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar, 2Dissanayake S.K. Wade M. Johnson C.E. O'Connell M.P. Leotlela P.D. French A.D. Shah K.V. Hewitt K.J. Rosenthal D.T. Indig F.E. Jiang Y. Nickoloff B.J. Taub D.D. Trent J.M. Moon R.T. Bittner M. Weeraratna A.T. J. Biol. Chem. 2007; 282: 17259-17271Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 3Dissanayake S.K. Olkhanud P.B. O'Connell M.P. Carter A. French A.D. Camilli T.C. Emeche C.D. Hewitt K.J. Rosenthal D.T. Leotlela P.D. Wade M.S. Yang S.W. Brant L. Nickoloff B.J. Messina J.L. Biragyn A. Hoek K.S. Taub D.D. Longo D.L. Sondak V.K. Hewitt S.M. Weeraratna A.T. Cancer Res. 2008; 68: 10205-10214Crossref PubMed Scopus (102) Google Scholar). In a decreased the motility of melanoma cells and cells are shown in data are Wnt5A In resulted in a in the of with the increasing the of Wnt5A by to the could the of the cells to a invasion invasion the of the of cells restored HSPG resulted in decreased motility and Wnt5A signaling in melanoma we which HSPG Wnt5A as with Wnt5A melanoma cells. and protein expression for glypicans and syndecans melanoma cell There expression of by and protein expression 1 and syndecan 4 expression demonstrated a with metastatic and syndecan demonstrated an by expression in cell We expression of syndecans in the data K.S. P. A. R. M. D. R. Cell Res. 2006; PubMed Scopus Google Scholar). a data of melanoma that can be metastatic potential K.S. P. A. R. M. D. R. Cell Res. 2006; PubMed Scopus Google Scholar). of this data that syndecans 1 and 4 are in patients with metastatic also as an of data could be in syndecan the protein syndecan 1 and 4 expression increase as cells metastatic the indicate syndecans the surface of the we cell surface for syndecan 4 and Wnt5A. These indicate that syndecan 4 and Wnt5A are the surface of the cell and levels in the metastatic cell We to syndecans Wnt5A in melanoma cells. Wnt5A to sugar the core we that be and our we In there are levels of Wnt5A, syndecan and syndecan 4 and In metastatic cells cells are shown as an this also for and syndecan 4 to a syndecan 1 could be the including in the Wnt5A with syndecan in and and syndecans have shown to and we that this also the in melanoma since syndecan 4 with the and that are These data indicate that Wnt5A and syndecans be as of a of Wnt and syndecan 1 and 4 correlated with increased melanoma cell and removal motility in melanoma syndecan 1 and syndecan 4 to of the core also decrease the motility of the cells. Following of siRNA syndecan 1 and 4 expression and levels as with the cells that with or siRNA in a invasion to and decreased the invasion of melanoma cells as with cells of and siRNA further invasion signaling in the of or siRNA could be restored the of the of Wnt5A could also the of melanoma as in the of the syndecan expression and cells with cells are and levels of Wnt5A, and treating the cells with Wnt5A invasion shown in and and The of to and cells restored be to the that the siRNA of the syndecans and increasing the of Wnt5A for signaling to be or be an of that can in the of These that and Wnt5A to melanoma cell The role of HSPGs in melanoma Previous studies have shown that are in cells characterized by metastatic and metastatic cells a heparan sulfate J. A. K. M. J. Google Scholar). that that or of HSPGs sulfate proteoglycans the cell surface of metastatic cells can be a of a metastatic In cell HSPGs have demonstrated to be important for Wnt signaling M. J. R. A. J. 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French A.D. Camilli T.C. Frank B.P. Earley R. Hoek K.S. Hasskamp J.H. Elias E.G. Taub D.D. Bernier M. Weeraratna A.T. J. Invest. Dermatol. 2009; 129: 1782-1789Abstract Full Text Full Text PDF PubMed Scopus (61) Google and (1Weeraratna A.T. Jiang Y. Hostetter G. Rosenblatt K. Duray P. Bittner M. Trent J.M. Cancer Cell. 2002; 1: 279-288Abstract Full Text Full Text PDF PubMed Scopus (790) Google Scholar). we have shown that this via Wnt5A activation of an M. J. A. B. T. A. D. and A. T. in These indicate that Wnt5A in a loop, to which Wnt5A, and increases the we of the and HSPGs Wnt5A and to the increasing the of In studies have shown that syndecan 4 can the of the of via of in signaling and and the of syndecan 4 decreases the of cells L. C. Larraín J. M. R. 2008; PubMed Scopus Google Scholar). In of in data in our a levels of syndecan 1 and 4 and the metastatic potential of melanoma cells. this and the that or siRNA in a decrease in motility and invasiveness of melanoma we that syndecan 1 and 4 also Wnt5A signaling and cellular invasion in melanoma. These data that HSPGs are for the of Wnt5A for signaling, the of HSPGs can be by increasing the of Wnt5A. for growth as of that the of since from data that the of Wnt5A that to and data from our laboratory indicate that of Wnt5A in our Wnt5A cells to or that indicate that the of Wnt5A and via for increased signaling and motility in melanoma M. J. A. B. T. A. D. and A. T. in we that for Wnt5A and The role of syndecans in melanoma In an syndecan 4 with Wnt5A, as a that in metastatic melanoma M. P. Y. Jiang Y. M. M. R. A. C. J. A. P. J. D. Dietrich K. C. M. D. Sondak PubMed Scopus Google Scholar), and studies have also as in melanoma J. L. A. Cell. 2006; PubMed Scopus Google Scholar). In the we this the protein and demonstrate that syndecan 1 and an important role in melanoma invasion, via role in the of Wnt5A known that syndecans can to to Wnt signaling L. C. Larraín J. M. R. 2008; PubMed Scopus Google Scholar), and also shown that of a component of Wnt signaling and that as a R. Cell Biol. 2006; PubMed Scopus Google Scholar). data a of and Wnt5A, the M. J. A. B. T. A. D. and A. T. in In studies have shown that syndecan 4 can the of the of via of in signaling and and the of syndecan 4 decreases the of cells L. C. Larraín J. M. R. 2008; PubMed Scopus Google Scholar). In of in data in our a levels of syndecan 1 and 4 and the metastatic potential of melanoma cells. this and the that syndecan 1 or 4 siRNA in a decrease in motility and invasiveness of melanoma we that syndecan 1 and 4 also Wnt5A signaling and cellular invasion in melanoma. from cell also a for syndecans cellular syndecan 4 for the invasion of G. R.A. J. Invest. Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). growth factor, the for syndecan 4 core protein expression G. R.A. J. Invest. Dermatol. Full Text Full Text PDF PubMed Scopus Google Scholar). 1 for invasion a and for the of P. J. Cell. 2008; PubMed Scopus Google Scholar). In melanoma the data are a shown to the surface of metastatic melanoma and of syndecan 1 shown to that syndecan 1 increase melanoma cell motility J. M. R. D.D. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). as side chains from the and this be a for the cell to to the of of syndecan that melanoma cells increase of or core protein expression of chains increase expression of syndecan 1 and as a to to this The role of since a that be a role the of syndecan 1 side that metastasis by heparan sulfate from the surface of melanoma cells as as of the to increased invasion of the cells to M. D. J. 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We for the with