title: Matrix metalloproteinase-9 is upregulated in nucleophosmin-anaplastic lymphoma kinase-positive anaplastic lymphomas and activated at the cell surface by the chaperone heat shock protein 90 to promote cell invasion.
abstract: Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(-) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL.
authors.affiliation: Département Oncogénèse, Université Toulouse III Paul-Sabatier, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lagarrigue
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Coronas
authors.forename: Damien
authors.initials: D
authors.lastname: Ramel
authors.forename: Georges
authors.initials: G
authors.lastname: Delsol
authors.forename: Hélène
authors.initials: H
authors.lastname: Tronchère
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.forename: Frédérique
authors.initials: F
authors.lastname: Gaits-Iacovoni
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D004151:Dipeptides; D004792:Enzyme Precursors; D018841:HSP90 Heat-Shock Proteins; D018960:Hyaluronan Receptors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C107953:RAC1 protein, human; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; D020830:rac1 GTP-Binding Protein