Ayakannu Thangesweran, Taylor Anthony H, Bari Monica, Mastrangelo Nicoletta, Maccarrone Mauro, Konje Justin C
Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, United Kingdom.
Gynaecology Oncology Cancer Centre, Liverpool Women's NHS Foundation Trust, Liverpool Women's Hospital, Liverpool, United Kingdom.
Front Oncol. 2019 Dec 19;9:1363. doi: 10.3389/fonc.2019.01363. eCollection 2019.
The concentrations of three -acylethanolamines (NAEs), anandamide (AEA), -oleoylethanolamide (OEA), and -palmitylethanolamide (PEA) are increased in the endometria of women with endometrial cancer (EC). It is widely accepted that plasma levels of these three NAEs are regulated by the actions of the rate-limiting enzymes -acylphoshatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), which are synthesizing and degradative, respectively. The expression and activity of these enzymes have not previously been studied in EC. FAAH activity in peripheral blood lymphocytes, and transcript and protein expression for FAAH and NAPE-PLD in EC tissues were measured using enzyme, quantitative RT-PCR, and histomorphometry (of immunoreactive tissue sections), respectively. Samples were from 6 post-menopausal women with atrophic endometria (controls) and 34 women with histologically diagnosed EC. Concentrations of the three NAEs also measured in plasma and tissues were correlated with lymphocytic FAAH activity and the NAPE-PLD and FAAH transcript and protein levels. Peripheral lymphocyte FAAH activity was unaffected in women with EC compared to controls. The FAAH transcript expression level was significantly ( < 0.0001) 75% lower in EC whilst NAPE-PLD levels were not significantly ( = 0.798) increased. In line with the transcript data, a significant ( < 0.0001) tumor type-dependent 70-90% decrease in FAAH protein and significant 4- to 14-fold increase in NAPE-PLD protein ( < 0.0001) was observed in the malignant tissue with more advanced disease having lower FAAH and higher NAPE-PLD expression than less advanced disease. Correlation analyses also confirmed that tissue NAE concentrations were inversely related to FAAH expression and directly correlated to NAPE-PLD expression and the NAPE-PLD/FAAH ratio. These data support our previous observation of tissue levels of AEA, OEA, and PEA and a role for NAE metabolism in the pathogenesis of EC.
在子宫内膜癌（EC）女性的子宫内膜中，三种酰基乙醇胺（NAEs），即花生四烯酸乙醇胺（AEA）、油酰乙醇胺（OEA）和棕榈酰乙醇胺（PEA）的浓度会升高。人们普遍认为，这三种NAEs的血浆水平受限速酶——分别起合成和降解作用的N-酰基磷脂酰乙醇胺特异性磷脂酶D（NAPE-PLD）和脂肪酸酰胺水解酶（FAAH）的作用调节。此前尚未在EC中研究过这些酶的表达和活性。分别使用酶法、定量逆转录聚合酶链反应（RT-PCR）和组织形态计量学（免疫反应组织切片）来测量外周血淋巴细胞中的FAAH活性以及EC组织中FAAH和NAPE-PLD的转录本和蛋白表达。样本来自6名绝经后萎缩性子宫内膜女性（对照组）和34名经组织学诊断为EC的女性。在血浆和组织中测量的三种NAEs浓度也与淋巴细胞FAAH活性以及NAPE-PLD和FAAH的转录本及蛋白水平相关。与对照组相比，EC女性的外周淋巴细胞FAAH活性未受影响。EC中FAAH转录本表达水平显著降低（P<0.0001），降低了75%，而NAPE-PLD水平未显著升高（P = 0.798）。与转录本数据一致，在恶性组织中观察到FAAH蛋白显著降低（P<0.0001），呈肿瘤类型依赖性，降低了70%至90%，而NAPE-PLD蛋白显著增加（P<0.0001），增加了4至14倍，疾病进展更严重的组织中FAAH表达低于疾病进展较轻的组织，而NAPE-PLD表达更高。相关性分析还证实，组织中NAE浓度与FAAH表达呈负相关，与NAPE-PLD表达以及NAPE-PLD/FAAH比值呈正相关。这些数据支持了我们之前关于AEA、OEA和PEA组织水平的观察结果以及NAE代谢在EC发病机制中的作用。
