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

Abstract

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.

DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway

“…In view of the fact that ANGPTL4 could regulate the migration and invasion ability of CRC cells, we asked whether ANGPTL4 was involved in the EMT process of CRC, using HCT116 and SW480 cells as models. Induction of molecules involved in the regulation of EMT was earlier shown as dependent on ANGPTL4 expression in head and neck squamous cell carcinoma cells 35 . PI3K/AKT, WNT and other signaling pathways are related to the deterioration of CRC and potential regulators of EMT process and we examined the protein levels of ERK, AKT, and WNT with the corresponding activated proteins to show that upon silencing ANGPTL4, the levels of p-ERK42/44 significantly increased in both cell lines.…”

Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer

“…In breast cancer, HDAC6 was frequently upregulated in the cancerassociated fibroblasts(CAFs) and increased the expression of COX-2/PGE2 by regulating STAT3 activation (20), leading to poor survival outcomes. In addition, the aberrant activation of EGF (21), KRAS (22), p38MAPK (23,24) signals, which frequently present in cancers, also induce COX-2 expression, thus to mediate immunosuppression.…”

Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer

“…And it has been reported that the high expression of HSPA5 can protect cancer cells from immune surveillance, and inhibition of its expression can promote cell apoptosis and inhibit tumor growth [ 24 , 25 ]. Angiopoietin-like4 (ANGPTL4) is highly expressed in various tumors, which is closely related to tumor growth and metastasis, such as hepatocellular carcinoma [ 26 ], breast cancer [ 27 ], head and neck squamous cell carcinoma [ 28 ] and melanoma [ 29 ]. And ANGPTL4 participates in the construction of GRG signature in lung adenocarcinoma to predict the survival and metastasis of patients [ 14 ].…”