title: Epidermal growth factor-induced cyclooxygenase-2 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation.
abstract: Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in many cancers, such as head and neck squamous cell carcinoma (HNSCC). However, whether the induction of cyclooxygenase-2 (COX-2) mediates EGF-enhanced HNSCC metastasis remains unclear. Interestingly, we found that EGF induced COX-2 expression mainly in HNSCC. The tumor cell transformation induced by EGF was repressed by COX-2 knockdown, and this repression was reversed by simultaneously treating the cells with EGF and prostaglandin E₂ (PGE₂). The down-regulation of COX-2 expression or inhibition of COX-2 activity significantly blocked EGF enhancement of cell migration and invasion, but the addition of PGE₂ compensated for this inhibitory effect in COX-2-knockdown cells. COX-2 depletion inhibited EGF-induced matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. The inhibitory effect of COX-2 depletion on MMPs and the fibronectin/Rac1/cdc42 axis were reversed by co-treatment with PGE₂. Furthermore, depletion of fibronectin impeded the COX-2-enhanced binding of HNSCC cells to endothelial cells and tumor cells metastatic seeding of the lungs. These results demonstrate that EGF-induced COX-2 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. The inhibition of COX-2 expression and activation may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Jinn-Yuan
authors.initials: JY
authors.lastname: Hsu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes and Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Kwang-Yu
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan 736, Taiwan, ROC.
authors.forename: Shang-Hung
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan 701, Taiwan, ROC.
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan, ROC.
authors.forename: Sheng-Tsung
authors.initials: ST
authors.lastname: Chang
authors.affiliation: Institute of Biochemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.|Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D066246:ErbB Receptors / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism*; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D000077195:Squamous Cell Carcinoma of Head and Neck; D015854:Up-Regulation
chemical_list: D005353:Fibronectins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors