Oleic acid-induced ANGPTL4 enhances head and neck squamous cell carcinoma anoikis resistance and metastasis via up-regulation of fibronectin

Cancer Lett. 2017 Feb 1;386:110-122. doi: 10.1016/j.canlet.2016.11.012. Epub 2016 Nov 16.


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.

Keywords: ANGPTL4; Fibronectin; MMP9; Metastasis; Oleate.

MeSH terms

  • Angiopoietin-Like Protein 4
  • Angiopoietins / genetics
  • Angiopoietins / metabolism*
  • Animals
  • Anoikis / drug effects*
  • Autocrine Communication / drug effects
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / secondary
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Coculture Techniques
  • Dose-Response Relationship, Drug
  • Epithelial-Mesenchymal Transition / drug effects
  • Fibronectins / genetics
  • Fibronectins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / secondary
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice, SCID
  • Neoplasm Invasiveness
  • Oleic Acid / toxicity*
  • RNA Interference
  • Signal Transduction / drug effects
  • Squamous Cell Carcinoma of Head and Neck
  • Time Factors
  • Transendothelial and Transepithelial Migration / drug effects
  • Transfection
  • Up-Regulation
  • Vimentin / metabolism
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / metabolism


  • ANGPTL4 protein, human
  • Angiopoietin-Like Protein 4
  • Angiopoietins
  • Fibronectins
  • RAC1 protein, human
  • Vimentin
  • Oleic Acid
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein