Research Papers:

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

Jinn-Yuan Hsu _, Kwang-Yu Chang, Shang-Hung Chen, Chung-Ta Lee, Sheng-Tsung Chang, Hung-Chi Cheng, Wen-Chang Chang and Ben-Kuen Chen

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Oncotarget. 2015; 6:1723-1739. https://doi.org/10.18632/oncotarget.2783

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Jinn-Yuan Hsu1, Kwang-Yu Chang2, Shang-Hung Chen3, Chung-Ta Lee4, Sheng-Tsung Chang5, Hung-Chi Cheng6, Wen-Chang Chang7, Ben-Kuen Chen7,8,9

1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC

2National 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

3Division of Hematology and Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan 736, Taiwan, ROC

4Department of Pathology, National Cheng Kung University Hospital, Tainan 701, Taiwan, ROC

5Department of Pathology, Chi-Mei Medical Center, Tainan 710, Taiwan, ROC

6Institute of Biochemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC

7Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC

8Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC

9Institute 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: [email protected]

Wen-Chang Chang, e-mail: [email protected]

Keywords: EGF, metastasis, COX-2, fibronectin

Received: August 28, 2014     Accepted: November 19, 2014     Published: December 22, 2014


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.

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