College of Medicine, Medical University of South Carolina, Charleston, SC, United States.
Key Laboratory of Green Chemical Engineering Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, China.
Front Immunol. 2024 Oct 16;15:1456719. doi: 10.3389/fimmu.2024.1456719. eCollection 2024.
Aberrant fatty acid metabolism (FAM) plays a critical role in the tumorigenesis of human malignancies. However, studies on its impact in lung adenocarcinoma (LUAD) are limited.
We developed a prognostic signature comprising 10 FAM-related genes (GPR115, SOAT2, CDH17, MOGAT2, COL11A1, TCN1, LGR5, SLC34A2, RHOV, and DKK1) using data from LUAD patients in The Cancer Genome Atlas (TCGA). This signature was validated using six independent LUAD datasets from the Gene Expression Omnibus (GEO). Patients were classified into high- and low-risk groups, and overall survival (OS) was compared by Kaplan-Meier analysis. The signature's independence as a prognostic indicator was assessed after adjusting for clinicopathological features. Receiver operating characteristic (ROC) analysis validated the signature. Tumor immune microenvironment (TIME) was analyzed using ESTIMATE and multiple deconvolution algorithms. Functional assays, including CCK8, cell cycle, apoptosis, transwell, and wound healing assays, were performed on MOGAT2-silenced H1299 cells using CRISPR/Cas9 technology.
Low-risk group patients exhibited decreased OS. The signature was an independent prognostic indicator and demonstrated strong risk-stratification utility for disease relapse/progression. ROC analysis confirmed the signature's validity across validation sets. TIME analysis revealed higher infiltration of CD8+ T cells, natural killers, and B cells, and lower tumor purity, stemness index, and tumor mutation burden (TMB) in low-risk patients. These patients also showed elevated T cell receptor richness and diversity, along with reduced immune cell senescence. High-risk patients exhibited enrichment in pathways related to resistance to immune checkpoint blockades, such as DNA repair, hypoxia, epithelial-mesenchymal transition, and the G2M checkpoint. LUAD patients receiving anti-PD-1 treatment had lower risk scores among responders compared to non-responders. MOGAT2 was expressed at higher levels in low-risk LUAD patients. Functional assays revealed that MOGAT2 knockdown in H1299 cells promoted proliferation and migration, induced G2 cell cycle arrest, and decreased apoptosis.
This FAM-related gene signature provides a valuable tool for prognostic stratification and monitoring of TIME and immunotherapy responses in LUAD. MOGAT2 is identified as a potential anti-tumor regulator, offering new insights into its role in LUAD pathogenesis.
异常脂肪酸代谢（FAM）在人类恶性肿瘤的发生中起着关键作用。然而，关于其在肺腺癌（LUAD）中的影响的研究有限。
我们使用来自癌症基因组图谱（TCGA）的 LUAD 患者的数据，开发了一个由 10 个 FAM 相关基因（GPR115、SOAT2、CDH17、MOGAT2、COL11A1、TCN1、LGR5、SLC34A2、RHOV 和 DKK1）组成的预后签名。该签名使用六个来自基因表达综合数据库（GEO）的独立 LUAD 数据集进行验证。根据 Kaplan-Meier 分析比较患者的高风险和低风险组，比较总生存期（OS）。调整临床病理特征后，评估该签名作为预后指标的独立性。接受者操作特征（ROC）分析验证了该签名。使用 ESTIMATE 和多种去卷积算法分析肿瘤免疫微环境（TIME）。使用 CRISPR/Cas9 技术在 MOGAT2 沉默的 H1299 细胞上进行 CCK8、细胞周期、凋亡、Transwell 和划痕愈合测定等功能测定。
低风险组患者的 OS 降低。该签名是一个独立的预后指标，对疾病复发/进展具有很强的风险分层能力。ROC 分析在验证组中证实了该签名的有效性。TIME 分析显示，低风险患者的 CD8+T 细胞、自然杀伤细胞和 B 细胞浸润较高，肿瘤纯度、干性指数和肿瘤突变负荷（TMB）较低。这些患者还显示出 T 细胞受体丰富度和多样性增加，以及免疫细胞衰老减少。高风险患者表现出对免疫检查点阻断耐药相关途径的富集，如 DNA 修复、缺氧、上皮-间充质转化和 G2M 检查点。接受抗 PD-1 治疗的 LUAD 患者中，与无反应者相比，应答者的风险评分较低。低风险 LUAD 患者的 MOGAT2 表达水平较高。功能测定显示，H1299 细胞中 MOGAT2 的敲低促进了增殖和迁移，诱导 G2 细胞周期停滞，并减少了凋亡。
这个与 FAM 相关的基因签名为 LUAD 的预后分层和监测 TIME 和免疫治疗反应提供了有价值的工具。MOGAT2 被鉴定为一种潜在的抗肿瘤调节剂，为其在 LUAD 发病机制中的作用提供了新的见解。
