title: Syndecan-1 and -4 differentially regulate oncogenic K-ras dependent cell invasion into collagen through α2β1 integrin and MT1-MMP.
abstract: Syndecans function as co-receptors for integrins on different matrixes. Recently, syndecan-1 has been shown to be important for α2β1 integrin-mediated adhesion to collagen in tumor cells by regulating cell adhesion and migration on two-dimensional collagen. However, the function of syndecans in supporting α2β1 integrin interactions with three-dimensional (3D) collagen is less well studied. Using loss-of-function and overexpression experiments we show that in 3D collagen syndecan-4 supports α2β1-mediated collagen matrix contraction. Cell invasion through type I collagen containing 3D extracellular matrix (ECM) is driven by α2β1 integrin and membrane type-1 matrix metalloproteinase (MT1-MMP). Here we show that mutational activation of K-ras correlates with increased expression of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4. While K-ras-induced α2β1 integrin and MT1-MMP are positive regulators of invasion, silencing and overexpression of syndecans demonstrate that these proteins inhibit cell invasion into collagen. Taken together, these data demonstrate the existence of a complex interplay between integrin α2β1, MT1-MMP, and syndecans in the invasion of K-ras mutant cells in 3D collagen that may represent a mechanism by which tumor cells become more invasive and metastatic.
authors.affiliation: VTT Biotechnology, Turku, Finland.
authors.forename: Karoliina
authors.initials: K
authors.lastname: Vuoriluoto
authors.forename: Gunilla
authors.initials: G
authors.lastname: Högnäs
authors.forename: Pipsa
authors.initials: P
authors.lastname: Meller
authors.forename: Kaisa
authors.initials: K
authors.lastname: Lehti
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005786:Gene Expression Regulation; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D006025:Glycosaminoglycans; D038982:Integrin alpha2beta1; C508241:SDC1 protein, human; C508304:SDC4 protein, human; D053668:Syndecan-1; D053671:Syndecan-4; D003094:Collagen; D053511:Matrix Metalloproteinase 14; D015689:Oncogene Protein p21(ras)