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Differential roles ...
Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression
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Nikolova, Viktoriya (author)
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Koo, Chuay-Yeng (author)
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Ibrahim, Sherif Abdelaziz (author)
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Wang, Zihua (author)
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- Spillmann, Dorothe (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi
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Dreier, Rita (author)
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Kelsch, Reinhard (author)
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Fischgräbe, Jeanett (author)
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Smollich, Martin (author)
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Rossi, Laura H (author)
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Sibrowski, Walter (author)
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Wülfing, Pia (author)
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Kiesel, Ludwig (author)
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Yip, George W (author)
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Götte, Martin (author)
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(creator_code:org_t)
- 2009-01-06
- 2009
- English.
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In: Carcinogenesis. - : Oxford University Press (OUP). - 1460-2180 .- 0143-3334. ; 30:3, s. 397-407
- Related links:
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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.
Keyword
- MEDICINE
- MEDICIN
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Nikolova, Viktor ...
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Koo, Chuay-Yeng
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Ibrahim, Sherif ...
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Wang, Zihua
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Spillmann, Dorot ...
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Dreier, Rita
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show more...
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Kelsch, Reinhard
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Fischgräbe, Jean ...
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Smollich, Martin
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Rossi, Laura H
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Sibrowski, Walte ...
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Wülfing, Pia
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Kiesel, Ludwig
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Yip, George W
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Götte, Martin
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show less...
- Articles in the publication
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Carcinogenesis
- By the university
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Uppsala University