Oleic acid-induced ANGPTL4 enhances head and neck squamous cell carcinoma anoikis resistance and metastasis via up-regulation of fibronectin. (1st February 2017)

• Record Type: Journal Article
• Authors: Shen, Chih-Jie; Chan, Shih-Hung; Lee, Chung-Ta; Huang, Wan-Chen; Tsai, Jhih-Peng; Chen, Ben-Kuen
• Is Part Of: Cancer letters. Volume 386(2017)
• Page Start: 110
• Page End: 122
• Publication Date: 2017-02-01
• Subjects: Oleate -- ANGPTL4 -- Metastasis -- MMP9 -- Fibronectin; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2016.11.012
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Obese patients have higher levels of free fatty acids (FFAs) in their plasma and a higher risk of cancer than their non-obese counterparts. However, the mechanisms involved in the regulation of cancer metastasis by FFAs remain unclear. In this study, we found that oleic acid (OA) induced angiopoietin-like 4 (ANGPTL4) protein expression and secretion and conferred anoikis resistance to head and neck squamous cell carcinomas (HNSCCs). The autocrine production of OA-induced ANGPTL4 further promoted HNSCC migration and invasion. In addition, the expression of peroxisome proliferator-activated receptor (PPAR) was essential for the OA-induced ANGPTL4 expression and invasion. The levels of OA-induced epithelial–mesenchymal transition markers, such as vimentin, MMP-9, and fibronectin and its downstream effectors Rac1/Cdc42, were significantly reduced in ANGPTL4-depleted cells. Knocking down fibronectin inhibited the expression of MMP-9 and repressed OA- and recombinant ANGPTL4-induced HNSCC invasion. On the other hand, ANGPTL4 siRNA inhibited OA-induced MMP-9 expression, which was reversed in fibronectin-overexpressing cells. Furthermore, the depletion of ANGPTL4 impeded the OA-primed metastatic seeding of tumor cells in the lungs. These results demonstrate that OA enhances HNSCC metastasis through the ANGPTL4/fibronectin/Rac1/Cdc42 and ANGPTL4/fibronectin/MMP-9 signaling axes. Highlights: OA-induced expression and autocrine production of ANGPTL4 regulates HNSCC migration and invasion. Anoikis resistance and adhesion to endothelial cells of OA-primed tumor cells are dependent on ANGPTL4. ANGPTL4 induces the expression of MMP-9 through the activation of the fibronectin/Rac1/Cdc42 signaling pathway in HNSCC.