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, Ben Kuen Chen

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1723-1739
Number of pages17
JournalOncotarget
Volume6
Issue number3
Publication statusPublished - 2015

Keywords

  • COX-2
  • EGF
  • Fibronectin
  • Metastasis

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Hsu, J. Y., Chang, K. Y., Chen, S. H., Lee, C. T., Chang, S. T., Cheng, H. C., Chang, W. C., & Chen, B. K. (2015). Epidermal growth factor-induced cyclooxygenase-2 enhances head and neck squamous cell carcinoma metastasis through fibronectin up-regulation. Oncotarget, 6(3), 1723-1739.