title: Hyaluronan-oligosaccharide-induced transcription of metalloproteases.
abstract: Activated dendritic epidermal Langerhans cells and metastatic tumour cells share many properties. Both cell types can invade the surrounding tissue, enter the lymphatic system and travel to regional lymph nodes. We have recently shown that fragments of the extracellular matrix component hyaluronan, which are typically produced at sites of inflammation, can activate dendritic cells. Upon activation, dendritic cells upregulate expression of matrix metalloproteases (MMPs). These observations prompted us to investigate whether exposure to hyaluronan fragments also induces MMP expression in tumour cells. Here, we report that MMP-9, MMP-13 and urokinase plasminogen activator are upregulated in murine 3LL tumour cells after exposure to mixed-size hyaluronan. Similarly upregulated MMP-9 and MMP-13 expression was observed in primary fibroblasts. By using size-fractionated hyaluronan preparations, we show that the enhanced expression of MMP-9 and MMP-13 is only induced by small hyaluronan (HA) fragments. Although our data suggest that HA-fragment-induced MMP-9 and MMP-13 expression is receptor mediated, they rule out an involvement of the hyaluronan receptors CD44, RHAMM/IHAP and TLR-4. Finally, we show that HA fragment-induced MMP-9 transcription is mediated via NF-kappa B. Our results suggest that the metastasis-associated HA degradation in tumours might promote invasion by inducing MMP expression.
authors.affiliation: Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, and University of Karlsruhe, Institute of Genetics, PO Box 3640, 76021 Karlsruhe, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Fieber
authors.forename: Petra
authors.initials: P
authors.lastname: Baumann
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Vallon
authors.forename: Christian
authors.initials: C
authors.lastname: Termeer
authors.forename: Jan C
authors.initials: JC
authors.lastname: Simon
authors.forename: Martin
authors.initials: M
authors.lastname: Hofmann
authors.forename: Peter
authors.initials: P
authors.lastname: Angel
authors.forename: Peter
authors.initials: P
authors.lastname: Herrlich
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Sleeman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism*; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000201:enzymology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C077089:CD44, keratinocyte; D006820:Hyaluronic Acid; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020780:Matrix Metalloproteinase 9