Wang Hui, Luo Shen, Yin Yue, Liu Yang, Sun Xiaomei, Qiu Ling, Wu Xin
Department of Gynecology, Obstetrics & Gynecology Hospital of Fudan University, Shanghai, China.
Cancer Cell Int. 2025 Jan 27;25(1):25. doi: 10.1186/s12935-025-03656-7.
Ovarian cancer (OC) remains a lethal gynecological malignancy with an alarming mortality rate, primarily attributed to delayed diagnosis and a lack of effective treatment modalities. Accumulated evidence highlights the pivotal role of reprogrammed lipid metabolism in fueling OC progression, however, the intricate underlying molecular mechanisms are not fully elucidated.
DLAT expression was assessed in OC tissues and cell lines by immunohistochemistry, western blot and qRT-PCR analysis. The effects of DLAT silencing on changes in lipid metabolism, cell viability, migration, and invasion were examined in SKOV3 and OVCAR3 cells using CCK-8, colony formation, Transwell migration and invasion, and wound-healing assays. GSEA analysis was used to examine the relationship between DLAT and lipid metabolism-related enzymes. Rescue experiments in which SREBP1 was overexpressed in DLAT-silenced cells were carried out. Western blot analysis was performed to determine whether the JAK2/STAT5 signaling pathway was involved in DLAT-regulated SREBP1 expression. Commercially available triglyceride and cholesterol detection kits, as well as Nile Red and Oil red O staining were used to measure lipid metabolism. A subcutaneous tumor model was established in BALB/c mice to confirm the role of the DLAT/SREBP1 axis in OC growth and metastasis in vivo.
DLAT expression was significantly upregulated in OC patient tissue and associated with poor prognosis. Silencing DLAT reduced lipid content and impaired OC cell proliferation, migration, and invasion. DLAT upregulated SREBP1 expression via the JAK2/STAT5 signaling pathway, enhancing expression of fatty acid synthesis enzymes and altering lipid metabolism. SREBP1 was essential for DLAT-dependent OC cell growth and metastasis both in vitro and in vivo.
This study uncovers a novel DLAT/JAK2/STAT5/SREBP1 axis that reprograms lipid metabolism in OC, providing insights into metabolic vulnerabilities and potential therapeutic targets for OC treatment.
卵巢癌（OC）仍然是一种致命的妇科恶性肿瘤，死亡率惊人，主要归因于诊断延迟和缺乏有效的治疗方式。越来越多的证据表明，重编程的脂质代谢在推动OC进展中起关键作用，然而，其复杂的潜在分子机制尚未完全阐明。
通过免疫组织化学、蛋白质印迹和qRT-PCR分析评估OC组织和细胞系中DLAT的表达。使用CCK-8、集落形成、Transwell迁移和侵袭以及伤口愈合试验，在SKOV3和OVCAR3细胞中检测DLAT沉默对脂质代谢、细胞活力、迁移和侵袭变化的影响。GSEA分析用于研究DLAT与脂质代谢相关酶之间的关系。在DLAT沉默的细胞中进行SREBP1过表达的拯救实验。进行蛋白质印迹分析以确定JAK2/STAT5信号通路是否参与DLAT调节的SREBP1表达。使用市售的甘油三酯和胆固醇检测试剂盒以及尼罗红和油红O染色来测量脂质代谢。在BALB/c小鼠中建立皮下肿瘤模型，以确认DLAT/SREBP1轴在体内OC生长和转移中的作用。
DLAT在OC患者组织中的表达显著上调，且与预后不良相关。沉默DLAT可降低脂质含量，并损害OC细胞的增殖、迁移和侵袭。DLAT通过JAK2/STAT5信号通路上调SREBP1的表达，增强脂肪酸合成酶的表达并改变脂质代谢。SREBP1对于体外和体内DLAT依赖的OC细胞生长和转移至关重要。
本研究揭示了一种新的DLAT/JAK2/STAT5/SREBP1轴，该轴可重编程OC中的脂质代谢，为OC治疗的代谢脆弱性和潜在治疗靶点提供了见解。
