Epidermal growth factor-induced ANGPTL4 enhances anoikis resistance and tumour metastasis in head and neck squamous cell carcinoma

Abstract

Epidermal growth factor (EGF) is important for cancer cell proliferation, angiogenesis and metastasis in many types of cancer. However, the mechanisms involved in EGF-induced head and neck squamous cell carcinoma (HNSCC) metastasis remain largely unknown. In this study, we reveal that angiopoietin-like 4 (ANGPTL4) plays an important role in the regulation of EGF-induced cancer metastasis. We showed that EGF-induced ANGPTL4 expression promoted anoikis resistance and cancer cell migration and invasion in HNSCC. In addition, depletion of ANGPTL4 inhibited EGF-induced cancer cell invasion. Autocrine production of EGF-induced ANGPTL4 regulated the expression of matrix metalloproteinases (MMPs). The induction of MMP-1 gene expression by ANGPTL4-activated integrin β1 signalling occurred through the AP-1 binding site in the MMP-1 gene promoter. Furthermore, down-regulation of MMP-1 impeded EGF- and recombinant ANGPTL4-enhanced HNSCC cell migration and invasion. Depletion of ANGPTL4 significantly blocked EGF-primed extravasation and metastatic seeding of tumour cells and MMP-1 expression in lungs. However, no effect of ANGPTL4 on tumour growth was observed. These results suggest that EGF-induced expression and autocrine production of ANGPTL4 enhances HNSCC metastasis via the up-regulation of MMP-1 expression. Inhibition of ANGPTL4 expression may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.

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

“…The peroxisome proliferator activated receptor (PPAR) binding sequence required for PGE 2 ‐induced ANGPTL4 promoter activity was found in a promoter reporter assay (Figure 4C). These results reinforce the essential roles of the ERK and PPAR signaling pathways in the regulation of PGE 2 ‐induced ANGPTL4 expression, as well as our previous studies in oleic acid‐ and EGF‐induced ANGPTL4 expression 5,6 …”

“…Our previous studies revealed that EGF induces the expression of COX‐2 or ANGPTL4, resulting in the promotion of tumor metastasis 5,30 . However, the reciprocal regulation of ANGPTL4 and COX‐2 in HNSCC metastasis remains poorly understood.…”

“…The pathogenesis of cancer metastasis involves several processes, including the loss of cellular adhesion, intravasation, survival in the circulation, extravasation, and eventual colonization in the distant metastatic organs 4 . The success of HNSCC cell extravasation is regulated by matricellular proteins such as angiopoietin‐like protein 4 (ANGPTL4), which is highly associated with tumor metastasis 5‐7 . Interestingly, upregulation of ANGPTL4 has been observed in esophageal SCC and oral tongue SCC 8,9 .…”

“…Interestingly, upregulation of ANGPTL4 has been observed in esophageal SCC and oral tongue SCC 8,9 . The expression of ANGPTL4 is also essential for EGF‐induced HNSCC metastasis 5 . Hypoxic condition‐dependent induction of ANGPTL4 by prostaglandin E 2 (PGE 2 ) promotes colorectal cancer progression 10 .…”

Expression of gallus epidermal growth factor (gEGF) with food-grade Lactococcus lactis expression system and its biological effects on broiler chickens

“…EGF has been shown to play an important role in gastrointestinal repair [2], gastric acid secretion [3], the regulation of embryo development [4,5], and the regulation of ion transport [6,7]. Recent studies have shown that EGF and EGFR may also be involved in tumorigenesis [8,9], and EGFR has been utilized as a target for cancer therapy. Thus, EGF is an influential molecule involved in multiple biological processes.…”