基于与氧化应激和磷脂代谢相关的基因的多组学分析揭示了胰腺癌的内在分子特征。
Multi-omics analyses based on genes associated with oxidative stress and phospholipid metabolism revealed the intrinsic molecular characteristics of pancreatic cancer.
发表日期:2023 Aug 21
作者:
Hongdong Wang, Hui Guo, Jiaao Sun, Yuefeng Wang
来源:
Cellular & Molecular Immunology
摘要:
氧化应激(OS)可以影响脂质代谢重编程,进而影响肿瘤细胞的生物活性。氧化应激和磷脂代谢(OSPM)如何影响胰腺癌(PC)的预后有待阐明。我们从先前发表的文献中获取了35个胰腺肿瘤样本、34个癌旁样本和31个正常胰腺组织的代谢数据。TCGA数据库提供了各种癌症样本。我们还在Gene Expression Omnibus(GEO)、International Cancer Genome Consortium(ICGC)、ArrayExpress和Genotype-Tissue Expression(GTEx)数据库中搜索了更多的PC和正常胰腺样本。对比PC与正常和癌旁组织中的代谢物。总结了在泛癌症中的关键OSPM基因的特征。我们利用随机生存森林分析和多变量Cox回归分析构建了一个OSPM相关的签名。根据该签名,我们将PC样本分为高风险和低风险亚组。进一步研究了肿瘤免疫微环境的失调情况。应用定量逆转录聚合酶链反应(qRT-PCR)对PC和正常组织中签名基因的表达进行了研究。进一步证明了这些基因的蛋白水平。在PC中,代谢组学研究揭示了PM的改变,而转录组学研究显示了OSPM相关基因的不同表达。然后,将930个PC样本分为三个具有不同预后的亚型,并开发了一个包含八个OSPM相关基因(即SLC2A1,MMP14,TOP2A,MBOAT2,ANLN,ECT2,SLC22A3和FGD6)的OSPM相关签名。通过该签名将样本分为高风险和低风险亚组,两者显示出不同的预后、免疫检查点基因表达水平、免疫细胞浸润和肿瘤微环境。风险评分与TIL、pDC、骨髓嗜酸细胞和T细胞共刺激的比例呈负相关。验证了签名中基因的表达水平在PC和正常样本中。与正常组织相比,PC样本中SLC2A1、MMP14、TOP2A、MBOAT2、ANLN和SLC22A3的蛋白水平上调。通过整合代谢组学和转录组学数据,我们研究了PC中OSPM的变化,并开发出了一个OSPM相关的签名,有助于PC的预后评估和个体化治疗。© 2023. Springer Nature Limited.
Oxidative stress (OS), which impacts lipid metabolic reprogramming, can affect the biological activities of cancer cells. How oxidative stress and phospholipid metabolism (OSPM) influence the prognosis of pancreatic cancer (PC) needs to be elucidated. The metabolic data of 35 pancreatic tumor samples, 34 para-carcinoma samples, and 31 normal pancreatic tissues were obtained from the previously published literature. Pan-cancer samples were obtained from The Cancer Genome Atlas (TCGA). And the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), ArrayExpress, and the Genotype-Tissue Expression (GTEx) databases were searched for more PC and normal pancreatic samples. The metabolites in PC were compared with normal and para-carcinoma tissues. The characteristics of the key OSPM genes were summarized in pan-cancer. The random survival forest analysis and multivariate Cox regression analysis were utilized to construct an OSPM-related signature. Based on this signature, PC samples were divided into high- and low-risk subgroups. The dysregulations of the tumor immune microenvironment were further investigated. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to investigate the expression of genes in the signature in PC and normal tissues. The protein levels of these genes were further demonstrated. In PC, metabolomic studies revealed the alteration of PM, while transcriptomic studies showed different expressions of OSPM-related genes. Then 930 PC samples were divided into three subtypes with different prognoses, and an OSPM-related signature including eight OSPM-related genes (i.e., SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, ECT2, SLC22A3, and FGD6) was developed. High- and low-risk subgroups divided by the signature showed different prognoses, expression levels of immune checkpoint genes, immune cell infiltration, and tumor microenvironment. The risk score was negatively correlated with the proportion of TIL, pDC, Mast cell, and T cell co-stimulation. The expression levels of genes in the signature were verified in PC and normal samples. The protein levels of SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, and SLC22A3 showed up-regulation in PC samples compared with normal tissues. After integrating metabolomics and transcriptomics data, the alterations in OSPM in PC were investigated, and an OSPM-related signature was developed, which was helpful for the prognostic assessment and individualized treatment for PC.© 2023. Springer Nature Limited.