PO.MCB09.05 · 分子与细胞生物学
LINE-1逆转座通过cPLA2/5-LOX轴驱动肺鳞状细胞癌中的脂质代谢重编程和免疫抑制
LINE-1 retrotransposition drives lipid metabolic reprogramming and immune suppression in lung squamous cell carcinoma via cPLA2/5-LOX axis
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摘要 Abstract
中文摘要
背景：长散在核元件-1（LINE-1；L1）逆转座在肺鳞状细胞癌（LUSC）中频繁发生，但其功能影响在很大程度上仍未阐明。我们此前鉴定出与不良预后相关的复发性L1-ATP8B1（L1插入ATP8B1）。鉴于ATP8B1在脂质稳态中的作用，我们假设L1-ATP8B1驱动脂质代谢重编程以促进LUSC进展。
方法：我们将癌症基因组图谱（TCGA）和验证队列的转录组学分析与靶向代谢组学、功能实验以及肿瘤-免疫细胞共培养系统相结合。通过在体外和体内模型中的基因扰动、药理学抑制和挽救实验进行了机制研究。
结果：基因本体（Gene Ontology）和KEGG富集分析显示L1-ATP8B1与脂质代谢失调相关，尤其是花生四烯酸（AA）代谢。代谢组学分析结果证实，在L1-ATP8B1过表达的细胞中，AA衍生的5-HETE和5-oxo-ETE（5-HETE的氧化代谢物）升高。在机制上，L1-ATP8B1上调PLA2G4和ALOX5的转录水平，以增强AA释放和5-HETE生成。药理学抑制其代谢酶胞质磷脂酶A₂（cPLA₂）和5-脂氧合酶（5-LOX）的活性可消除肿瘤进展，而外源性5-oxo-ETE则挽救了该效应。此外，我们发现L1-ATP8B1通过募集髓源性抑制细胞（MDSCs）诱导免疫抑制。共培养实验表明，5-oxo-ETE通过激活非经典NF-κB信号增强MDSCs的免疫抑制功能，从而抑制T细胞增殖和IFN-gamma产生——这一效应可通过抑制5-LOX而逆转。
结论：我们的研究结果揭示了一个此前未被认识的L1/cPLA2/5-LOX/NF-κB轴，将脂质代谢重编程与LUSC免疫逃逸联系起来。L1-ATP8B1通过脂质介质驱动肿瘤侵袭性和免疫抑制。靶向该通路是克服LUSC免疫耐药的一种有前景的治疗策略。
查看英文原文 English abstract
Background : Long interspersed nuclear element-1 (LINE-1; L1) retrotransposition is frequent in lung squamous cell carcinoma (LUSC), yet its functional impact remains largely unelucidated. We previously identified recurrent L1-ATP8B1 (L1 insertion in ATP8B1) associated with poor prognosis. Given ATP8B1's role in lipid homeostasis, we hypothesize L1-ATP8B1 drives lipid metabolic reprogramming to promote LUSC progression.
Methods : We integrated transcriptomic analyses of The Cancer Genome Atlas (TCGA) and validation cohorts with targeted metabolomics, functional assays, and tumor-immune cell co-culture systems. Mechanistic studies were conducted via genetic perturbation, pharmacologic inhibition, and rescue experiments in both in vitro and in vivo models.
Results : Gene Ontology and KEGG enrichment analysis revealed L1-ATP8B1 correlated with deregulated lipid metabolism, particularly arachidonic acid (AA) metabolism. Metabolomic profiling results confirmed elevated AA-derived 5-HETE and 5-oxo-ETE (the oxidation metabolite of 5-HETE) in L1-ATP8B1-over-expressing cells. Mechanistically, L1-ATP8B1 up-regulated the transcriptional levels of PLA2G4 and ALOX5 to enhance AA release and 5-HETE generation. Pharmacologic inhibition of the activity of their metabolic enzymes cytosolic phospholipase A₂ (cPLA₂) and 5-lipoxygenase (5-LOX) abrogated tumor progression, whereas exogenous 5-oxo-ETE rescued the effects. Further, we found L1-ATP8B1 induced immune suppression by recruiting myeloid-derived suppressor cells (MDSCs). Co-culture experiments demonstrated 5-oxo-ETE enhanced the immunosuppressive function of MDSCs by activating non-canonical NF-κB signaling, thereby inhibiting T cell proliferation and IFN-gamma production-an effect reversed by 5-LOX inhibition.
Conclusions : Our findings uncover a previously unrecognized L1/cPLA2/5-LOX/NF-κB axis linking lipid metabolic reprogramming to LUSC immune evasion. L1-ATP8B1 drives tumor aggressiveness and immune suppression via lipid mediators. Targeting this pathway is a promising therapeutic strategy to overcome immune resistance in LUSC.
利益披露 Disclosure
R. Zhang, None..
W. Tian, None..
P. Liu, None..
J. Yu, None.