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|Title:||Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression||Authors:||Nikolova, V.
|Issue Date:||2009||Citation:||Nikolova, V., Koo, C.-Y., Ibrahim, S.A., Wang, Z., Spillmann, D., Dreier, R., Kelsch, R., Fischgräbe, J., Smollich, M., Rossi, L.H., Sibrowski, W., Wülfing, P., Kiesel, L., Yip, G.W., Götte, M. (2009). Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis 30 (3) : 397-407. ScholarBank@NUS Repository. https://doi.org/10.1093/carcin/bgp001||Abstract:||The heparan sulfate proteoglycan syndecan-1 (Sdc1) modulates cell proliferation, adhesion, migration and angiogenesis. Proteinase-mediated shedding converts Sdc1 from a membrane-bound coreceptor into a soluble effector capable of binding the same ligands. In breast carcinomas, Sdc1 overexpression correlates with poor prognosis and an aggressive phenotype. To distinguish between the roles of membrane-bound and shed forms of Sdc1 in breast cancer progression, human MCF-7 breast cancer cells were stably transfected with plasmids overexpressing wild-type (WT), constitutively shed and uncleavable forms of Sdc1. Overexpression of WT Sdc1 increased cell proliferation, whereas overexpression of constitutively shed Sdc1 decreased proliferation. Fibroblast growth factor-2-mediated mitogen-activated protein kinase signaling was reduced following small-interfering RNA (siRNA)-mediated knockdown of Sdc1 expression. Constitutively, membrane-bound Sdc1 inhibited invasiveness, whereas soluble Sdc1 promoted invasion of MCF-7 cells into matrigel matrices. The latter effect was reversed by the matrix metalloproteinase inhibitors N isobutyl-N-(4-methoxyphenylsufonyl) glycyl hydroxamic acid and tissue inhibitor of metalloproteinase (TIMP)-1. Affymetrix microarray analysis identified TIMP-1, Furin and urokinase-type plasminogen activator receptor as genes differentially regulated in soluble Sdc1-overexpressing cells. Endogenous TIMP-1 expression was reduced in cells overexpressing soluble Sdc1 and increased in those overexpressing the constitutively membrane-bound Sdc1. Moreover, E-cadherin protein expression was downregulated in cells overexpressing soluble Sdc1. Our results suggest that the soluble and membrane-bound forms of Sdc1 play different roles at different stages of breast cancer progression. Proteolytic conversion of Sdc1 from a membrane-bound into a soluble molecule marks a switch from a proliferative to an invasive phenotype, with implications for breast cancer diagnostics and potential glycosaminoglycan-based therapies. © The Author 2009. Published by Oxford University Press. All rights reserved.||Source Title:||Carcinogenesis||URI:||http://scholarbank.nus.edu.sg/handle/10635/120682||ISSN:||01433334||DOI:||10.1093/carcin/bgp001|
|Appears in Collections:||Staff Publications|
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