miR-1275靶向FAAH协同调控AEA/LPA信号参与胃癌脂质代谢重编程机制及标志物研究

脂质代谢调控与胃癌发生发展关系密切。我们前期经转录组测序联合PCR筛选出脂肪酸酰胺水解酶（FAAH）在胃癌中高表达。功能试验证实FAAH显著促进胃癌细胞增殖和转移。生物信息学和荧光素酶试验证实FAAH是miR-1275的靶基因，且miR-1275可逆转FAAH介导的促癌效应。经脂质代谢组学检测，干扰FAAH后一些关键脂质信号分子发生显著变化，如花生四烯酸乙醇胺（AEA）和磷脂酰乙醇胺（PE）等抑癌分子含量增加，而花生四烯酸（AA）和溶血磷脂酸（LPA）等促癌分子含量减少，前列腺素E2（PGE2）等炎性介质含量下降。我们推测，胃癌中低丰度miR-1275失去靶向抑制FAAH的能力，高表达的FAAH通过对AEA/LPA信号的协同调控介导胃癌脂质代谢重编程，进而激活COX-2/PGE2信号轴促进胃癌进展。本研究还将探讨miR-1275及FAAH作为胃癌潜在标志物的临床价值，为胃癌诊疗提供新靶标。

The regulation of lipid metabolism is closely related to the occurrence and development of gastric cancer (GC). We previously performed the whole transcriptome sequencing and combined the PCR to screen out the significantly highly expressed FAAH in GC tissues. Functional tests confirmed that FAAH significantly promoted cell proliferation and metastasis. Besides, bioinformatics analysis and dual-luciferase reporter assay confirmed that miR-1275 could complementarily bind to the 3'-UTR of FAAH, thus reversing the tumor-promoting effects mediated by FAAH. Lipidomics showed that some key lipid signals changed significantly after silencing FAAH, such as increased arachidonoyl ethanolamide (AEA) and phosphatidylethanolamine (PE), as well as decreased arachidonic acid (AA) and lysophosphatidic acid (LPA) in GC cells. Moreover, FAAH interference reduced the content of inflammatory mediators represented by prostaglandin E2 (PGE2) in the cell supernatant. Thus, we speculate that the low abundance of miR-1275 in GC loses control of FAAH, and subsequent high expression of FAAH mediates lipid metabolism reprogramming through the coordinated regulation of AEA/LPA signals, which finally activates the COX-2/PGE2 axis to promote GC progression. This study will also explore the clinical value of FAAH as a potential biomarker and provide new targets for the diagnosis and treatment of GC.