BK21 PLUS Team, College of Pharmacy, The Catholic University of Korea, Bucheon 14662, Korea.
Korea Hydro & Nuclear Power (KHNP) Central Research Institute, Daejeon 34101, Korea.
Cells. 2021 Mar 4;10(3):558. doi: 10.3390/cells10030558.
Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)--glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl--glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.
氧化磷脂在调节细胞内稳态和疾病进展方面发挥着重要的生理和病理作用已广为人知。然而，它们在癌症转移中的作用尚未完全被理解。在这项研究中，通过免疫印迹和共聚焦分析，研究了氧化磷脂酰胆碱（如 1-棕榈酰-2-（5-氧戊酰基）-甘油-3-磷酸胆碱（POVPC））对癌细胞上皮间质转化（EMT）和自噬的影响。通过划痕实验和 Transwell 迁移/侵袭实验分析转移。通过 LC-MS/MS 分析测定从患者获得的肿瘤组织中 POVPC 和 1-棕榈酰-2-戊二酰基-甘油磷酸胆碱（PGPC）的浓度。POVPC 诱导 EMT，导致人肝癌细胞（HepG2）和人乳腺癌细胞（MCF7）迁移和侵袭增加。POVPC 通过 AMPK-mTOR 通路诱导自噬流。自噬的药理学抑制或 siRNA 敲低减少了 POVPC 处理的 HepG2 和 MCF7 细胞的迁移和侵袭。在患者来源的肝内胆管癌组织的 II 期，POVPC 和 PGPC 水平大大增加。恶性乳腺癌组织中的 PGPC 水平高于相邻非肿瘤组织。结果表明，氧化磷脂通过促进自噬，增加了癌细胞的转移潜力，从而介导 EMT。这表明在肿瘤微环境中积累的氧化磷脂在肿瘤发生和转移的调节中具有正调控作用。
