Abstract |
It has been established that fragmented hyaluronic acid (HA), but not native high molecular weight HA, can induce angiogenesis, cell proliferation and migration. We have studied the outside-in signal transduction pathways responsible for fragmented HA-mediated cancer cell invasion. In our study, we have studied the effects of CD44 stimulation by ligation with HA upon the expression of matrix metalloproteinases (MMPs)-2 and -9 as well as urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1) and the subsequent induction of invasion of human chondrosarcoma cell line HCS-2/8. Our study indicates that (i) CD44 stimulation by fragmented HA upregulates expression of uPA and uPAR mRNA and protein but does not affect MMPs secretion or PAI-1 mRNA expression; (ii) the effects of HA fragments are critically HA size dependent: high molecular weight HA is inactive, but lower molecular weight fragmented HA (Mr 3.5 kDa) is active; (iii) cells can bind avidly Mr 3.5 kDa fragmented HA through a CD44 molecule, whereas cells do not effectively bind higher Mr HA; (iv) a fragmented HA induces phosphorylation of MAP kinase proteins (MEK1/2, ERK1/2 and c-Jun) within 30 min; (v) CD44 is critical for the response (activation of MAP kinase and upregulation of uPA and uPAR expression); and (vi) cell invasion induced by CD44 stimulation with a fragmented HA is inhibited by anti-CD44 mAb, MAP kinase inhibitors, neutralizing anti-uPAR pAb, anti-catalytic anti-uPA mAb or amiloride. Therefore, our study represents the first report that CD44 stimulation induced by a fragmented HA results in activation of MAP kinase and, subsequently, enhances uPA and uPAR expression and facilitates invasion of human chondrosarcoma cells.
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Authors | Hiroshi Kobayashi, Mika Suzuki, Naohiro Kanayama, Takashi Nishida, Masaharu Takigawa, Toshihiko Terao |
Journal | International journal of cancer
(Int J Cancer)
Vol. 102
Issue 4
Pg. 379-89
(Dec 01 2002)
ISSN: 0020-7136 [Print] United States |
PMID | 12402308
(Publication Type: Journal Article)
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Copyright | Copyright 2002 Wiley-Liss, Inc. |
Chemical References |
- Adjuvants, Immunologic
- Enzyme Inhibitors
- Hyaluronan Receptors
- PLAUR protein, human
- Plasminogen Activator Inhibitor 1
- RNA, Messenger
- Receptors, Cell Surface
- Receptors, Urokinase Plasminogen Activator
- Tyrosine
- Hyaluronic Acid
- Calcium-Calmodulin-Dependent Protein Kinases
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases
- Urokinase-Type Plasminogen Activator
- Matrix Metalloproteinases
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Topics |
- Adjuvants, Immunologic
(metabolism, pharmacology)
- Bone Neoplasms
(drug therapy, genetics, metabolism)
- Calcium-Calmodulin-Dependent Protein Kinases
(metabolism)
- Chondrosarcoma
(drug therapy, genetics, metabolism)
- Enzyme Inhibitors
(pharmacology)
- Gene Expression Regulation
- Humans
- Hyaluronan Receptors
(metabolism)
- Hyaluronic Acid
(pharmacology)
- MAP Kinase Signaling System
(physiology)
- Matrix Metalloproteinases
(metabolism)
- Mitogen-Activated Protein Kinase 3
- Mitogen-Activated Protein Kinases
(metabolism)
- Neoplasm Invasiveness
- Phosphorylation
- Plasminogen Activator Inhibitor 1
(metabolism)
- RNA, Messenger
(metabolism)
- Receptors, Cell Surface
(genetics, metabolism)
- Receptors, Urokinase Plasminogen Activator
- Signal Transduction
(drug effects)
- Tumor Cells, Cultured
(drug effects)
- Tyrosine
(metabolism)
- Up-Regulation
- Urokinase-Type Plasminogen Activator
(genetics, metabolism)
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