Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 200032 Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, 200032 Shanghai, China.
Front Biosci (Landmark Ed). 2024 Mar 21;29(3):119. doi: 10.31083/j.fbl2903119.
Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor in urgent need of novel diagnostics, prognostic markers, and treatments. Eukaryotic translation initiation factor 2 subunits (EIF2Ss), comprising Eukaryotic translation initiation factor 2 subunit alpha EIF2S1), Eukaryotic translation initiation factor 2 subunit beta (EIF2S2), and Eukaryotic translation initiation factor 2 subunit gamma (EIF2S3), is a family of eukaryotic initiation factors that participate in early protein synthesis and are crucial for tumor initiation and progression. However, the role of EIF2Ss in PAAD has yet to be reported. The aim of this study was therefore to analyze EIF2Ss in relation to the diagnosis, prognosis, and treatment of PAAD.
The cancer genome atlas (TCGA) database was used to investigate gene expression and patient survival. Gene alterations, immune cell infiltration, and immune checkpoints in PAAD were also evaluated. Univariate and multivariate analysis, nomograms, calibration curves, and Decision Curve Analysis (DCA) diagrams were used to develop and evaluate a prediction model for patient outcome. Single-cell RNA-seq (scRNA) analysis, functional enrichment, co-IP assay, mass spectrometry, and western blot were used to study the relationship between EIF2Ss and c-myc in PAAD.
EIF2Ss are over-expressed in PAAD tissue and are associated with poor prognosis. The frequency of , , and gene alteration in PAAD was 0.2%, 0.4%, and 0.2%, respectively. High EIF2Ss expression was associated with Th2 cell infiltration, whereas low expression was associated with pDC infiltration. Moreover, EIF2Ss expression was positively correlated with the expression of the , , , , , and checkpoints. A prediction model developed using EIF2Ss and important clinicopathologic features showed good predictive value for the overall survival of PAAD patients. ScRNA-Seq data showed that EIF2Ss was associated with enrichment for endothelial cells, fibroblasts, malignant cells, and ductal cells. EIF2Ss expression was also correlated with adipogenesis, interferon-alpha response, epithelial-mesenchymal transition, myc targets, G2M checkpoint, oxidative phosphorylation, and hypoxia. Functional enrichment analysis of EIF2Ss showed a close correlation with the myc pathway, and interactions between EIF2Ss and c-myc were confirmed by co-IP assay and mass spectrometry. Importantly, knockdown of c-myc decreased the expression of EIF2S1, EIF2S2, and EIF2S3 in PAAD cells.
EIF2Ss were found to have significant clinical implications for the prognosis and treatment of PAAD. Inhibition of c-myc caused the downregulation of EIF2S1, EIF2S2, and EIF2S3 expression.
胰腺导管腺癌（PAAD）是一种高度恶性的肿瘤，迫切需要新的诊断、预后标志物和治疗方法。真核翻译起始因子 2 亚基（EIF2Ss）由真核翻译起始因子 2 亚基α（EIF2S1）、真核翻译起始因子 2 亚基β（EIF2S2）和真核翻译起始因子 2 亚基γ（EIF2S3）组成，是参与早期蛋白质合成的真核起始因子家族的一部分，对于肿瘤的发生和发展至关重要。然而，EIF2Ss 在 PAAD 中的作用尚未被报道。因此，本研究旨在分析 EIF2Ss 与 PAAD 的诊断、预后和治疗的关系。
使用癌症基因组图谱（TCGA）数据库研究基因表达和患者生存情况。还评估了 PAAD 中的基因改变、免疫细胞浸润和免疫检查点。使用单变量和多变量分析、列线图、校准曲线和决策曲线分析（DCA）图来开发和评估预测患者结局的模型。单细胞 RNA-seq（scRNA）分析、功能富集、免疫共沉淀测定、质谱和 Western blot 用于研究 EIF2Ss 与 PAAD 中 c-myc 的关系。
EIF2Ss 在 PAAD 组织中过度表达，与预后不良相关。PAAD 中 、 和 基因改变的频率分别为 0.2%、0.4%和 0.2%。高 EIF2Ss 表达与 Th2 细胞浸润有关，而低表达与 pDC 浸润有关。此外，EIF2Ss 表达与 、 、 、 、 检查点的表达呈正相关。使用 EIF2Ss 和重要的临床病理特征开发的预测模型对 PAAD 患者的总生存率具有良好的预测价值。scRNA-Seq 数据显示，EIF2Ss 与内皮细胞、成纤维细胞、恶性细胞和导管细胞的富集有关。EIF2Ss 的表达也与脂肪生成、干扰素-α反应、上皮-间充质转化、myc 靶点、G2M 检查点、氧化磷酸化和缺氧有关。EIF2Ss 的功能富集分析显示与 myc 通路密切相关，免疫共沉淀测定和质谱证实了 EIF2Ss 与 c-myc 之间的相互作用。重要的是，c-myc 的敲低降低了 PAAD 细胞中 EIF2S1、EIF2S2 和 EIF2S3 的表达。
EIF2Ss 对 PAAD 的预后和治疗具有重要的临床意义。抑制 c-myc 导致 EIF2S1、EIF2S2 和 EIF2S3 的表达下调。
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