Epidermal growth factor-induced cyclooxygenase-2 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation

// Jinn-Yuan Hsu 1 , Kwang-Yu Chang 2 , Shang-Hung Chen 3 , Chung-Ta Lee 4 , Sheng-Tsung Chang 5 , Hung-Chi Cheng 6 , Wen-Chang Chang 7 , Ben-Kuen Chen 7, 8, 9 1 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC 2 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 3 Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan 736, Taiwan, ROC 4 Department of Pathology, National Cheng Kung University Hospital, Tainan 701, Taiwan, ROC 5 Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan, ROC 6 Institute of Biochemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC 7 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC 8 Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC 9 Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC Correspondence to: Ben-Kuen Chen, e-mail: bkchen58@mail.ncku.edu.tw Wen-Chang Chang, e-mail: wcchang@tmu.edu.tw Keywords: EGF, metastasis, COX-2, fibronectin Received: August 28, 2014      Accepted: November 19, 2014      Published: December 22, 2014 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 E 2 (PGE 2 ). 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 PGE 2 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 PGE 2 . 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.