Cell surface syndecan-1 contributes to binding and function of macrophage migration inhibitory factor (MIF) on epithelial tumor cells

Biochim Biophys Acta. 2016 Apr;1863(4):717-26. doi: 10.1016/j.bbamcr.2016.02.003. Epub 2016 Feb 4.

Abstract

Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinases involved in this process. Finally, MIF induced the chemotactic migration of A549 cells, wound closure and invasion into matrigel without affecting cell proliferation. These MIF-induced responses were abrogated by heparin or by silencing of syndecan-1. Thus, our study indicates that syndecan-1 on epithelial tumor cells promotes MIF binding and MIF-mediated cell migration. This may represent a relevant mechanism through which MIF enhances tumor cell motility and metastasis.

Keywords: Chemokine; Heparin; Macrophage migration inhibitory factor; Metalloproteinase; Proteoglycan; Syndecan; Tumor cell migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion
  • Cell Membrane / metabolism
  • Cell Movement
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • HEK293 Cells
  • Heparitin Sulfate / metabolism
  • Humans
  • Intramolecular Oxidoreductases / metabolism*
  • Intramolecular Oxidoreductases / physiology*
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Macrophage Migration-Inhibitory Factors / physiology*
  • Neoplasm Metastasis
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Protein Binding
  • Syndecan-1 / metabolism
  • Syndecan-1 / physiology*
  • Tumor Cells, Cultured

Substances

  • Macrophage Migration-Inhibitory Factors
  • Syndecan-1
  • Heparitin Sulfate
  • Intramolecular Oxidoreductases
  • MIF protein, human