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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
Syndecan-1 (CD138) modulates triple-negative breast cancer stem cell properties via regulation of LRP-6 and IL-6-mediated STAT3 signaling
PLoS ONE, Volume 8, No. 12, Article e85737, Year 2013
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Description
Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches. © 2013 Ibrahim et al.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3877388/bin/pone.0085737.s001.ppt
https://efashare.b-cdn.net/share/pmc/articles/PMC3877388/bin/pone.0085737.s002.ppt
Authors & Co-Authors
Ibrahim, Sherif Abdelaziz
Germany, Munster
Universitätsklinikum Münster
Egypt, Giza
Faculty of Science
Hassan, Hebatallah H.M.
Germany, Munster
Universitätsklinikum Münster
Egypt, Giza
Faculty of Science
Vilardo, Laura
Italy, Rome
Consiglio Nazionale Delle Ricerche
Kumar, Sampath Katakam
Germany, Munster
Universitätsklinikum Münster
Kumar, Archana Vijaya
Germany, Munster
Universitätsklinikum Münster
Kelsch, Reinhard
Germany, Munster
Universitätsklinikum Münster
Schneider, Cornelia
Germany, Munster
Universitätsklinikum Münster
Kiesel, Ludwig
Germany, Munster
Universitätsklinikum Münster
Eich, Hans Theodor T.
Germany, Munster
Universitätsklinikum Münster
Zucchi, Ileana
Italy, Rome
Consiglio Nazionale Delle Ricerche
Reinbold, Rolland A.
Italy, Rome
Consiglio Nazionale Delle Ricerche
Grève, Burkhard
Germany, Munster
Universitätsklinikum Münster
Götte, Martin
Germany, Munster
Universitätsklinikum Münster
Statistics
Citations: 101
Authors: 13
Affiliations: 3
Identifiers
Doi:
10.1371/journal.pone.0085737
e-ISSN:
19326203
Research Areas
Cancer
Study Design
Cross Sectional Study