title: Syndecan-1 modulates β-integrin-dependent and interleukin-6-dependent functions in breast cancer cell adhesion, migration, and resistance to irradiation.
abstract: Syndecan-1 is a cell surface heparan sulfate proteoglycan with various biological functions relevant to tumor progression and inflammation, including cell-cell adhesion, cell-matrix interaction, and cytokine signaling driving cell proliferation and motility. Syndecan-1 is a prognostic factor in breast cancer, and has a predicitive value for neodadjuvant chemotherapy. It is still poorly understood how syndecan-1 integrates matrix-dependent and cytokine-dependent signaling processes in the tumor microenvironment. Here, we evaluated the potential role of syndecan-1 in modulating matrix-dependent breast cancer cell migration in the presence of interleukin-6, and its potential involvement in resistance to irradiation in vitro. MDA-MB-231 breast cancer cells were transiently transfected with syndecan-1 small interfering RNA or control reagents, and this was followed by stimulation with interleukin-6 or irradiation. Cellular responses were monitored by adhesion, migration and colony formation assays, as well as analysis of cell signaling. Syndecan-1 depletion increased cell adhesion to fibronectin. Increased migration on fibronectin was significantly suppressed by interleukin-6, and GRGDSP peptides inhibited both adhesion and migration. Interleukin-6-induced activation of focal adhesion kinase and reduction of constitutive nuclear factor kappaB signaling were decreased in syndecan-1-deficient cells. Focal adhesion kinase hyperactivation in syndecan-1-depleted cells was associated with dramatically reduced radiation sensitivity. We conclude that loss of syndecan-1 leads to enhanced activation of β1 -integrins and focal adhesion kinase, thus increasing breast cancer cell adhesion, migration, and resistance to irradiation. Syndecan-1 deficiency also attenuates the modulatory effect of the inflammatory microenvironment constituent interleukin-6 on cancer cell migration.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Münster, Germany.
authors.forename: Hebatallah
authors.initials: H
authors.lastname: Hassan
authors.forename: Burkhard
authors.initials: B
authors.lastname: Greve
authors.forename: Mauro S G
authors.initials: MS
authors.lastname: Pavao
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kiesel
authors.forename: Sherif A
authors.initials: SA
authors.lastname: Ibrahim
authors.forename: Martin
authors.initials: M
authors.lastname: Götte
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor / Q000528:radiation effects; D054443:Cell Migration Assays; D002465:Cell Movement; D004789:Enzyme Activation; D005260:Female; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D017785:Photons; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D053668:Syndecan-1 / Q000378:metabolism*; D014162:Transfection; D059016:Tumor Microenvironment; D014410:Tumor Stem Cell Assay
chemical_list: D005353:Fibronectins; D039081:Integrin alpha5beta1; D015850:Interleukin-6; D016328:NF-kappa B; D009842:Oligopeptides; D034741:RNA, Small Interfering; C508241:SDC1 protein, human; D053668:Syndecan-1; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human