Shen Chih-Jie, Chan Shih-Hung, Lee Chung-Ta, Huang Wan-Chen, Tsai Jhih-Peng, Chen Ben-Kuen
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.
Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, ROC.
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.
肥胖患者血浆中的游离脂肪酸（FFA）水平高于非肥胖患者，且患癌风险也更高。然而，FFA调控癌症转移的机制仍不清楚。在本研究中，我们发现油酸（OA）可诱导血管生成素样4（ANGPTL4）蛋白的表达和分泌，并赋予头颈部鳞状细胞癌（HNSCC）抗失巢凋亡能力。OA诱导的ANGPTL4的自分泌进一步促进了HNSCC的迁移和侵袭。此外，过氧化物酶体增殖物激活受体（PPAR）的表达对于OA诱导的ANGPTL4表达和侵袭至关重要。在ANGPTL4缺失的细胞中，OA诱导的上皮-间质转化标志物（如波形蛋白、基质金属蛋白酶-9和纤连蛋白）及其下游效应分子Rac1/Cdc42的水平显著降低。敲低纤连蛋白可抑制基质金属蛋白酶-9的表达，并抑制OA和重组ANGPTL4诱导的HNSCC侵袭。另一方面，ANGPTL4 siRNA抑制OA诱导的基质金属蛋白酶-9表达，而在纤连蛋白过表达的细胞中这种抑制作用被逆转。此外，ANGPTL4的缺失阻碍了OA引发的肿瘤细胞在肺部的转移定植。这些结果表明，OA通过ANGPTL4/纤连蛋白/Rac1/Cdc42和ANGPTL4/纤连蛋白/基质金属蛋白酶-9信号轴增强HNSCC转移。
