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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.

机构信息

Department of Hepatobiliary Pancreatic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.

Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.

出版信息

Sci Rep. 2023 Aug 21;13(1):13564. doi: 10.1038/s41598-023-40560-4.

DOI:10.1038/s41598-023-40560-4
PMID:37604837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10442332/
Abstract

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.

摘要

氧化应激（OS）影响脂质代谢重编程，从而影响癌细胞的生物活性。需要阐明氧化应激和磷脂代谢（OSPM）如何影响胰腺癌（PC）的预后。从之前发表的文献中获得了 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。泛癌样本来自癌症基因组图谱（TCGA）。还从基因表达综合（GEO）、国际癌症基因组联盟（ICGC）、ArrayExpress 和基因型-组织表达（GTEx）数据库中搜索了更多的 PC 和正常胰腺样本。比较了 PC 中的代谢物与正常和癌旁组织。总结了泛癌中关键 OSPM 基因的特征。随机生存森林分析和多变量 Cox 回归分析用于构建 OSPM 相关特征。基于该特征，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。进行了定量逆转录聚合酶链反应（qRT-PCR）以研究特征中基因在 PC 和正常组织中的表达。进一步验证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 样本分为三种具有不同预后的亚型，并开发了包括 8 个 OSPM 相关基因（即 SLC2A1、MMP14、TOP2A、MBOAT2、ANLN、ECT2、SLC22A3 和 FGD6）的 OSPM 相关特征。由特征划分的高风险和低风险亚组显示出不同的预后、免疫检查点基因的表达水平、免疫细胞浸润和肿瘤微环境。风险评分与 TIL、pDC、Mast cell 和 T 细胞共刺激的比例呈负相关。在 PC 和正常样本中验证了特征中基因的表达水平。与正常组织相比，PC 样本中 SLC2A1、MMP14、TOP2A、MBOAT2、ANLN 和 SLC22A3 的基因表达水平上调。整合代谢组学和转录组学数据后，研究了 PC 中 OSPM 的变化，并开发了 OSPM 相关特征，有助于 PC 的预后评估和个体化治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/b8bbbb50a118/41598_2023_40560_Fig9_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/b8bbbb50a118/41598_2023_40560_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/dd12f08f0a31/41598_2023_40560_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/7a339b7fe535/41598_2023_40560_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/49dec3fdd776/41598_2023_40560_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/8dbfc9d915ec/41598_2023_40560_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/d1eb37fd60ca/41598_2023_40560_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/5180c2a22723/41598_2023_40560_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/0f9459b81c87/41598_2023_40560_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5553/10442332/b8bbbb50a118/41598_2023_40560_Fig9_HTML.jpg

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引用本文的文献

[1]
Oxidative Stress: Signaling Pathways, Biological Functions, and Disease.

MedComm (2020). 2025-7-1

[2]
Pancreatic cancer subtyping - the keystone of precision treatment.

Front Immunol. 2025-4-8

[3]
Pan-cancer analysis predicts MBOAT2 as a potential new ferroptosis related gene immune checkpoint.

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[4]
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[5]
Comprehensive multi-omics profiling identifies novel molecular subtypes of pancreatic ductal adenocarcinoma.

Genes Dis. 2023-10-14

本文引用的文献

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Front Endocrinol (Lausanne). 2023

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Determination and characterization of molecular heterogeneity and precision medicine strategies of patients with pancreatic cancer and pancreatic neuroendocrine tumor based on oxidative stress and mitochondrial dysfunction-related genes.

Front Endocrinol (Lausanne). 2023

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