Expression and Function of the Endocannabinoid Modulating Enzymes Fatty Acid Amide Hydrolase and N-Acylphosphatidylethanolamine-Specific Phospholipase D in Endometrial Carcinoma
Expression and Function of the Endocannabinoid Modulating Enzymes Fatty Acid Amide Hydrolase and N-Acylphosphatidylethanolamine-Specific Phospholipase D in Endometrial Carcinoma
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DOI：
10.3389/fonc.2019.01363
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发表时间：
2019-12-19
影响因子：
4.7
通讯作者：
Konje, Justin C.
中科院分区：
文献类型：
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作者：
Ayakannu, Thangesweran;Taylor, Anthony H.;Konje, Justin C.
背景：子宫内膜癌(EC)患者子宫内膜中N-酰基乙醇胺(NAES)、烷基酰胺(AEA)、N-油酰乙醇胺(OEA)和N-棕榈酰乙醇胺(PEA)浓度升高。人们普遍认为，这三种NAE的血浆水平分别由合成和降解的限速酶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)调节。这些酶的表达和活性以前在EC中还没有被研究过。方法：应用酶标法、定量RT-PCR法和组织形态计量学方法分别检测外周血淋巴细胞FAAH活性、食管癌组织中FAAH和NAPE-PLD基因的转录和蛋白表达。样本来自6名患有萎缩性子宫内膜的绝经后妇女(对照组)和34名组织学诊断为EC的妇女。血浆和组织中三种NAE的浓度也与淋巴细胞FAAH活性以及NAPE-PLD和FAAH转录本和蛋白水平相关。结果：与对照组相比，EC患者外周血淋巴细胞FAAH活性无明显变化。在EC中，FAAHmRNA的表达水平显著降低(p<；0.0001)，而NAPE-pld的表达水平并未显著升高(p=0.798)。与转录数据一致的是，在FAAH表达较低而NAPE-PLD表达较低的晚期恶性组织中，FAAH蛋白显著(p<；0.0001)下降70-90%，NAPE-pld蛋白显著增加4-14倍(p<；0.0001)。相关分析还证实，组织NAE浓度与FAAH表达呈负相关，与NAPE-PLD表达和NAPE-PLD/FAAH比值呈正相关。结论：这些数据支持我们先前对组织中AEA、OEA和PEA水平的观察，以及NAE代谢在EC发病机制中的作用。
Background: The concentrations of three N-acylethanolamines (NAEs), anandamide (AEA), N-oleoylethanolamide (OEA), and N-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 N-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. Methods: 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. Results: Peripheral lymphocyte FAAH activity was unaffected in women with EC compared to controls. The FAAH transcript expression level was significantly (p < 0.0001) 75% lower in EC whilst NAPE-PLD levels were not significantly (p = 0.798) increased. In line with the transcript data, a significant (p < 0.0001) tumor type-dependent 70-90% decrease in FAAH protein and significant 4- to 14-fold increase in NAPE-PLD protein (p < 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. Conclusion: 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.