Angiopoietin-like 4 (ANGPTL4) contributes to Epidermal growth factor (EGF)-stimulated metastasis of head and neck squamous cell carcinoma (HNSCC)

• Main Authors: Yu-HanLiao, 廖禹涵
• Other Authors: Ben-Kuen Chen
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/39x4qf

博士 === 國立成功大學 === 生物科技與產業科學系 === 107 === Most head and neck cancers are squamous cell types, also called head and neck squamous cell carcinoma (HNSCC). About 75% of head and neck cancer is caused by the use of alcohol or tobacco. Other risk factors such as betel quid, some types of human papillomavirus, radiation exposure, specific workplace exposures, and the Epstein-Barr virus. Early period HNSCC is treated comparatively well with a single-modality therapy (either surgery or radiation alone). However, almost 66% of patients current with advanced sickness, and less than 30% of these patients can be cured. The treatment of advanced HNSCC frequently requires multimodality therapy and involves significant toxicity. HNSCC can spread and metastasize to other parts of the body, for example the lymph nodes or lungs. Metastasis is an complex sequential process that demands a discrete population of tumor cells to have the capacity to intravasate from the original tumor into systemic circulation, exist and survive in circulation, extravasate at a distant site, growth spurt and proliferate in a foreign hostile environment. Once HNSCC spreads, patients with metastatic disease have very poor prognosis with a survival rate of fewer than a year. Metastasis remains a main cause of decease in patients with HNSCC. There are many molecular markers that could be linchpin players in important procedures of HNSCC progression, including EGF, EGFR, BCL-2, BAX, JUN, VEGFA, MMP2 and MMP9. Most notably, epidermal growth factor receptor (EGFR), also known as ErbB1/HER1, is a member of the ErbB family of receptor tyrosine kinases. EGFR is overexpressed in several epithelial malignancies, including HNSCC, which exhibits EGFR overexpression in up to 90% of tumors. EGFR act a pivotal role in HNSCC growth, invasion, metastasis, and angiogenesis. EGFR ligands such as epidermal growth factor (EGF) play a major role in the malignant transformation of HNSCC. EGFR contributes to a metastatic HNSCC tumor cell phenotype through regulation of invasion, migration, and anoikis. ANGPTL4 (Angiopoietin Like Protein 4), which is also called (ARP4, FIAF, HFARP, NL2, PGAR, pp1158) is a protein coding gene. It is a secreted protein with a coiled-coil Nterminal domain and a fibrinogen-like C-terminal domain. The ANGPTL4 protein belongs to a superfamily of secreted proteins structurally related to factors modulating angiogenesis known as angiopoietins that may play as a regulator of angiogenesis and modulate tumorigenesis. Initially, ANGPTL4 was evaluated as an adipokine exclusive involved in lipid metabolism because of its widespread expression in liver and adipose tissue. ANGPTL4 is an endogenous inhibitor of lipoprotein lipase that modulates lipid standards, coronary atherosclerosis risk, and nutrient partitioning. Hypoxia-induced ANGPTL4 protein expression in endothelial cells. Studies show that ANGPTL4 mediates the cross talk between metabolic syndromes, for example diabetes, obesity, and cancer, through regulation of its expression by PPARs, and studies have also demonstrated that ANGPTL4 may be involved in cancer progression and metastasis. For example, ANGPTL4 boosts the malice phenotype of primary melanomas with risky of metastasizing to the brain, and it could be also promoted metastsis and curb the apoptosis of colorectal cancer cells. The induction of ANGPTL4 by the cytokine TGFβ via the Smad signaling pathway in the breast tumor microenvironment trigger cancer cells for metastasis to the lungs. HNSCC is an invasive life-threatening disease related to high mortality rates. Efforts have been made to probe the molecular mechanisms that promoted the initiation and progression of HNSCC. However, the functional role and regulatory mechanism of ANGPTL4 in the development of EGF-enhanced HNSCC metastasis is still unclear. We confirm that EGF stimulates the protein secretion of ANGPTL4 in HNSCC. In this study, we demonstrate that ANGPTL4 expression enhances EGF-promoted head and neck cancer cell anoikis resistance. In addition to EGF-, ANGPTL4 enhances HNSCC malignant behavior including migration, invasion and anoikis resistance. Furthermore, we demonstrated that ANGPTL4 expression and secretion by EGF is involved in EGF-promoted HNSCC migration, invasion, and transendothelial invasion. ANGPTL4 alone can also influence HNSCC migration, invasion, and transendothelial invasion. In addition, EGF-stimulated anoikis-resistant tumor cell interaction with endothelial cells is significantly repressed by abolishing the expression of ANGPTL4. Down-regulation of ANGPTL4 has been shown to block EGF-induced protein expression and enzyme activation of matrix metalloproteinases-1 (MMP-1) involved in head and neck cancer cell migration, invasion, and metastasis. Furthermore, ANGPTL4 activates the expression of c-Jun affect activator protein-1 (AP-1) binding to the MMP-1 promoter via the integrin β1 (ITGβ1) signal pathway. The c-Jun signaling pathway is essential for ANGPTL4-regulated expression of MMP-1 and is involved in the EGF/ANGPTL4/MMP-1 axis in HNSCC. EGF-induced ANGPTL4 autocrine production stimulates tumor-endothelial cell interactions, which then facilitates the ability of tumor cells to infiltrate into blood vessels. The repression of ANGPTL4 significantly suppresses EGF-stimulated HNSCC both in terms of extravasation and metastatic seeding into the lungs. All in all, these results indicate that ANGPTL4 facilitates EGF-promoted cancer metastasis via increasing the expression of MMP-1 in HNSCC. Both the protein secretion and autocrine production of ANGPTL4 are important markers in epidermal growth factor receptor (EGFR)-mediated HNSCC metastasis.