Chan Shih-Hung, Tsai Jhih-Peng, Shen Chih-Jie, Liao Yu-Han, Chen Ben-Kuen
Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, People's Republic of China.
Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 701, Taiwan, People's Republic of China.
Oncotarget. 2017 Jun 20;8(25):41364-41378. doi: 10.18632/oncotarget.17326.
The association between metabolic diseases and the risk of developing cancer is emerging. However, the impact of long pentraxin-3 (PTX3) on dyslipidemia-associated tumor metastasis remains unknown. In this study, we found that oleate induced PTX3 expression and secretion through the activation of Akt/NF-κB pathway in head and neck squamous cell carcinomas (HNSCCs). The activation of NF-κB was essential for the oleate-induced stabilization of PTX3 mRNA. In addition, both the depletion of PTX3 and the inhibition of NF-κB significantly inhibited oleate-induced tumor cell migration and invasion. The enhancement of binding between tumor and endothelial cells was observed in oleate-treated cells but not in the depletion and neutralization of PTX3 with siPTX3 and anti-PTX3 antibodies, respectively. The levels of oleate-induced epithelial-mesenchymal transition (EMT) markers, such as vimentin and MMP-3, were significantly reduced in PTX3-depleted cells. Knocking down vimentin also repressed oleate-induced HNSCC invasion. Furthermore, the depletion of PTX3 blocked the oleate-primed metastatic seeding of tumor cells in the lungs. These results demonstrate that oleate enhances HNSCC metastasis through the PTX3/vimentin signaling axes. The inhibition of PTX3 could be a potential strategy for the treatment of dyslipidemia-mediated HNSCC metastasis.
代谢性疾病与患癌风险之间的关联正在显现。然而，长五聚体蛋白3（PTX3）对血脂异常相关肿瘤转移的影响仍不清楚。在本研究中，我们发现油酸通过激活头颈部鳞状细胞癌（HNSCCs）中的Akt/NF-κB通路诱导PTX3表达和分泌。NF-κB的激活对于油酸诱导的PTX3 mRNA稳定至关重要。此外，PTX3的缺失和NF-κB的抑制均显著抑制了油酸诱导的肿瘤细胞迁移和侵袭。在油酸处理的细胞中观察到肿瘤细胞与内皮细胞之间的结合增强，但在用siPTX3和抗PTX3抗体分别耗尽和中和PTX3的细胞中未观察到这种增强。在PTX3缺失的细胞中，油酸诱导的上皮-间质转化（EMT）标志物（如波形蛋白和MMP-3）水平显著降低。敲低波形蛋白也抑制了油酸诱导的HNSCC侵袭。此外，PTX3的缺失阻止了油酸引发的肿瘤细胞在肺部的转移定植。这些结果表明，油酸通过PTX3/波形蛋白信号轴增强HNSCC转移。抑制PTX3可能是治疗血脂异常介导的HNSCC转移的潜在策略。
