Journal Article

Epidermal growth factor‐induced COX‐2 regulates metastasis of head and neck squamous cell carcinoma through upregulation of angiopoietin‐like 4

Shen, Chih‐Jie, Chiang, Kuo‐Hwa, Chen, Ben‐Kuen, Wu, Pei‐Ting, Hsu, Jinn‐Yuan, Tsai, Jhih‐Peng, Chang, Wen‐Chang, Chang, Ting‐Wei, Shieh, Jiunn‐Min

2020

Overview

Epidermal growth factor receptor (EGFR) expression and activation are the major causes of metastasis in cancers such as head and neck squamous cell carcinoma (HNSCC). However, the reciprocal effect of EGF‐induced COX‐2 and angiopoietin‐like 4 (ANGPTL4) on HNSCC metastasis remains unclear. In this study, we revealed that the expression of ANGPTL4 is essential for COX‐2‐derived prostaglandin E2 (PGE2)‐induced tumor cell metastasis. We showed that EGF‐induced ANGPTL4 expression was dramatically inhibited with the depletion and inactivation of COX‐2 by knockdown of COX‐2 and celecoxib treatment, respectively. Prostaglandin E2 induced ANGPTL4 expression in a time‐ and dose‐dependent manners in various HNSCC cell lines through the ERK pathway. In addition, the depletion of ANGPTL4 and MMP1 significantly impeded the PGE2‐induced transendothelial invasion ability of HNSCC cells and the binding of tumor cells to endothelial cells. The induction of molecules involved in the regulation of epithelial‐mesenchymal transition was also dependent on ANGPTL4 expression in PGE2‐treated cells. The depletion of ANGPTL4 further blocked PGE2‐primed tumor cell metastatic seeding of lungs. These results indicate that the EGF‐activated PGE2/ANGPTL4 axis enhanced HNSCC metastasis. The concurrent expression of COX‐2 and ANGPTL4 in HNSCC tumor specimens provides insight into potential therapeutic targets for the treatment of EGFR‐associated HNSCC metastasis. Metastasis is the major cause of cancer mortality. However, there is no significant improvement in treating advanced head and neck cancer. Our finding indicates that the monitoring levels of angiopoietin‐like 4 (ANGPTL4) are necessary for the treatment of inflammation‐ and/or growth factor‐mediated advanced or metastatic head and neck cancer. The expression of ANGPTL4, a potent angiogenetic factor in cancer, is essential for head and neck cancer metastasis caused by inflammatory response and growth factor stimulation. Therefore, the use of antiinflammatory medicines such as nonsteroidal antiinflammatory drugs and targeting ANGPTL4 could be considered as alternative approaches in treating and preventing the recurrence of head and neck cancer.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Angiopoietin / Angiopoietin-Like Protein 4 - metabolism / ANGPTL4 / Animals / Biomarkers / Celecoxib / Cell adhesion & migration / Cell culture / Cell Line, Tumor / Cyclooxygenase 2 - metabolism / EGF / Endothelial cells / Epidermal growth factor / Epidermal Growth Factor - metabolism / Epidermal growth factor receptors / Gene Expression Regulation, Neoplastic - physiology / Head & neck cancer / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / Heterografts / HNSCC / Humans / Kinases / Laboratory animals / Male / Mesenchyme / Metabolic pathways / Metastases / Metastasis / Mice / Mice, SCID / Mortality / Neoplasm Invasiveness - pathology / Original / PGE2 / Prostaglandin E2 / Proteins / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - pathology / Therapeutic applications / Tumor cells / Up-Regulation