Lv Xinting, Li Chunping, Wang Zhaohao, Xue Kun
Department of Neurosurgery, Yantaishan Hospital Affiliated to Binzhou Medical University, No. 10087, Keji Avenue, Laishan District, Yantai, 264003, Shandong, China.
Department of Critical Care Medicine, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai, 264000, Shandong, China.
Appl Biochem Biotechnol. 2025 Sep 2. doi: 10.1007/s12010-025-05362-6.
Fatty acid metabolism is critical for numerous biological processes involved in the pathogenesis of glioma. This study aimed to survey the role of ORMDL sphingolipid biosynthesis regulator 2 (ORMDL2) in fatty acid metabolism of glioma cells. The expression of ORMDL2 in glioma and its association with survival rate was detected using The Cancer Genome Atlas (TCGA) data and Kaplan-Meier survival curve. The effect of ORMDL2 on glioma was explored by culturing human glioma cells in vitro and constructing mouse glioma models. Cell proliferation, apoptosis, and fatty acid metabolism were detected by CCK-8, flow cytometry, colony formation assay, BODIPY staining, immunohistochemistry, western blotting, and qRT-PCR. ORMDL2 was upregulated in lower-grade glioma (LGG) and glioblastoma multiforme (GBM) tissues as compared to brain tissues collected from patients with traumatic craniotomy. Its high expression was associated with poor patient survival. ORMDL2 silencing inhibited glioma cell proliferation, lipid droplet formation, and promoted apoptosis in vitro. Silencing of ORMDL2 in xenograft mouse model inhibited tumor volume and weight. Additionally, ORMDL2 silencing decreased the levels of fatty acid metabolism-related factors FASN, ACC1 and SCD1, and the phosphorylation of a downstream effector of mTORC1 (S6K). Moreover, mTORC1 agonist MHY1485 reversed the inhibitory effect of ORMDL2 silencing on U87 cell fatty acid metabolism; mTORC1 inhibitor rapamycin reversed the promoting effect of ORMDL2 overexpression on U251 cell fatty acid metabolism. To conclude, this study demonstrated the high expression of ORMDL2 in glioma and its tumor-promoting action by activating mTORC1-mediated fatty acid metabolism.
脂肪酸代谢对于胶质瘤发病机制中涉及的众多生物学过程至关重要。本研究旨在探讨ORMDL鞘脂生物合成调节因子2（ORMDL2）在胶质瘤细胞脂肪酸代谢中的作用。使用癌症基因组图谱（TCGA）数据和Kaplan-Meier生存曲线检测ORMDL2在胶质瘤中的表达及其与生存率的关系。通过体外培养人胶质瘤细胞和构建小鼠胶质瘤模型来探究ORMDL2对胶质瘤的影响。采用CCK-8、流式细胞术、集落形成试验、BODIPY染色、免疫组织化学、蛋白质免疫印迹法和qRT-PCR检测细胞增殖、凋亡和脂肪酸代谢。与外伤性开颅手术患者的脑组织相比，ORMDL2在低级别胶质瘤（LGG）和多形性胶质母细胞瘤（GBM）组织中上调。其高表达与患者预后不良相关。ORMDL2沉默抑制了胶质瘤细胞增殖、脂滴形成，并在体外促进了细胞凋亡。在异种移植小鼠模型中沉默ORMDL2可抑制肿瘤体积和重量。此外，ORMDL2沉默降低了脂肪酸代谢相关因子FASN、ACC1和SCD1的水平，以及mTORC1下游效应器（S6K）的磷酸化水平。此外，mTORC1激动剂MHY1485逆转了ORMDL2沉默对U87细胞脂肪酸代谢的抑制作用；mTORC1抑制剂雷帕霉素逆转了ORMDL2过表达对U251细胞脂肪酸代谢的促进作用。总之，本研究证明了ORMDL2在胶质瘤中的高表达及其通过激活mTORC1介导的脂肪酸代谢发挥的促肿瘤作用。
