title: Oleic acid-induced ANGPTL4 enhances head and neck squamous cell carcinoma anoikis resistance and metastasis via up-regulation of fibronectin.
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.
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan, ROC.
authors.forename: Chih-Jie
authors.initials: CJ
authors.lastname: Shen
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Shih-Hung
authors.initials: SH
authors.lastname: Chan
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, Tainan 701, Taiwan, ROC.
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC; Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC.
authors.forename: Wan-Chen
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Jhih-Peng
authors.initials: JP
authors.lastname: Tsai
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC; Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC; Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, ROC; Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan, ROC. Electronic address: bkchen58@mail.ncku.edu.tw.
authors.forename: Ben-Kuen
authors.initials: BK
authors.lastname: Chen
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D019898:Autocrine Communication / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D019301:Oleic Acid / Q000633:toxicity*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D005353:Fibronectins; C107953:RAC1 protein, human; D014746:Vimentin; D019301:Oleic Acid; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
keywords: ANGPTL4; Fibronectin; MMP9; Metastasis; Oleate