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一种用于预测膀胱尿路上皮癌患者总生存期的新型铁死亡相关基因模型。

A Novel Ferroptosis-Related Gene Model for Overall Survival Predictions of Bladder Urothelial Carcinoma Patients.

作者信息

Zhang Min, Zhang Xin, Yu Minghang, Zhang Wei, Zhang Di, Zeng Song, Wang Xi, Hu Xiaopeng

机构信息

Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Institute of Urology, Capital Medical University, Beijing, China.

出版信息

Front Oncol. 2021 Jul 27;11:698856. doi: 10.3389/fonc.2021.698856. eCollection 2021.


DOI:10.3389/fonc.2021.698856
PMID:34386423
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8353278/
Abstract

INTRODUCTION: Bladder cancer is the most common urinary tract malignancy, and 90% of bladder tumors are urothelial cell carcinomas. Ferroptosis is a new form of cell death discovered in recent years, which is an iron-dependent form of cell death characterized by the lethal intracellular accumulation of lipid-based reactive oxygen species. Ferroptosis is considered to be a double-edged sword for cancer and cancer therapy. MATERIALS AND METHODS: In the current study, expression profiles of bladder cancer (BLCA) specimens were obtained from The Cancer Genome Atlas (TCGA) RNA-Seq database. Ferroptosis-related genes were downloaded from the FerrDb website. The ferroptosis-related differentially expressed genes (DEGs) which were related to overall survival (OS) were first identified. The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression methods were utilized to develop a ferroptosis-related prognostic model (FRPM). In addition, a nomogram model based on FRPM and clinicopathological features was successfully constructed and validated. In addition, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) methods were utilized in this study in order to compare the DEGs between the high-risk and low-risk groups. This study also adopted RT-qPCR, CCK-8 assay, and scratch assay methods to perform experimental verification processes. RESULTS AND DISCUSSION: A 7-gene FRPM was constructed in this research investigation in order to stratify the patients into two groups according to their risk scores. The results of this study's survival analysis and time-dependent receiver operating characteristic (ROC) analysis demonstrated that the model had achieved a stable performance level. This multivariate Cox regression results revealed that the FRPM was an independent prognostic predictor for the OS of BLCA patients and the results were displayed using a nomogram. In addition, the ROC analysis, concordance index (C-index), calibration plots, and decision curve analysis (DCA) curves further indicated that this study's nomogram method enabled valuable prediction results. The functional enrichment analysis results suggested that the DEGs between the high- and low-risk groups played vital roles in the progression of the ferroptosis. Also, the ssGSEA indicated that the immune status was different between the two groups. This study found that the RT-qPCR results had confirmed the differential expressions of DEGs in the tissue samples, and the CCK-8 assay and scratch assay results confirmed the promoting effects of SCD on the proliferation and migration of tumor cells. CONCLUSIONS: This study defined a novel prognostic model of seven ferroptosis-related genes, which proved to be independently associated with the OS of BLCA. A nomogram method was developed for the purpose of providing further insight into the accurate predictions of BLCA prognoses.

摘要

引言:膀胱癌是最常见的泌尿系统恶性肿瘤,90%的膀胱肿瘤为尿路上皮细胞癌。铁死亡是近年来发现的一种新的细胞死亡形式,是一种铁依赖性的细胞死亡,其特征是细胞内基于脂质的活性氧致命性积累。铁死亡被认为是癌症及癌症治疗的一把双刃剑。 材料与方法:在本研究中,从癌症基因组图谱(TCGA)RNA测序数据库中获取膀胱癌(BLCA)标本的表达谱。从FerrDb网站下载铁死亡相关基因。首先鉴定与总生存期(OS)相关的铁死亡相关差异表达基因(DEG)。利用最小绝对收缩和选择算子(LASSO)和多变量Cox回归方法建立铁死亡相关预后模型(FRPM)。此外,成功构建并验证了基于FRPM和临床病理特征的列线图模型。另外,本研究采用基因本体(GO)、京都基因与基因组百科全书(KEGG)和单样本基因集富集分析(ssGSEA)方法,比较高风险组和低风险组之间的DEG。本研究还采用逆转录定量聚合酶链反应(RT-qPCR)、细胞计数试剂盒-8(CCK-8)检测和划痕试验方法进行实验验证。 结果与讨论:本研究构建了一个包含7个基因的FRPM,以便根据风险评分将患者分为两组。本研究生存分析和时间依赖性受试者工作特征(ROC)分析结果表明,该模型达到了稳定的性能水平。多变量Cox回归结果显示,FRPM是BLCA患者OS的独立预后预测因子,结果用列线图展示。此外,ROC分析、一致性指数(C指数)、校准图和决策曲线分析(DCA)曲线进一步表明,本研究的列线图方法能得出有价值的预测结果。功能富集分析结果表明,高风险组和低风险组之间的DEG在铁死亡进展中起重要作用。此外,ssGSEA表明两组之间的免疫状态不同。本研究发现,RT-qPCR结果证实了组织样本中DEG的差异表达,CCK-8检测和划痕试验结果证实了硬脂酰辅酶A去饱和酶(SCD)对肿瘤细胞增殖和迁移的促进作用。 结论:本研究定义了一种新的由7个铁死亡相关基因组成的预后模型,该模型被证明与BLCA的OS独立相关。开发了一种列线图方法,以进一步深入了解BLCA预后的准确预测。

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引用本文的文献

[1]
Predicting survival in bladder cancer with a novel apoptotic gene-related prognostic model.

Discov Oncol. 2024-11-24

[2]
Liproxstatin-1 Alleviated Ischemia/Reperfusion-Induced Acute Kidney Injury via Inhibiting Ferroptosis.

Antioxidants (Basel). 2024-1-31

[3]
Identification of Immune-Related Subtypes and Construction of a Novel Prognostic Model for Bladder Urothelial Cancer.

Biomolecules. 2022-11-11

[4]
Lycorine suppresses cell growth and invasion via down-regulation of NEDD4 ligase in bladder cancer.

Am J Cancer Res. 2022-10-15

[5]
Prognostic, Clinicopathological, and Function of Key Cuproptosis Regulator in Clear Cell Renal Cell Carcinoma.

Genes (Basel). 2022-9-26

[6]
Identification and Validation of a Novel Ferroptotic Prognostic Genes-Based Signature of Clear Cell Renal Cell Carcinoma.

Cancers (Basel). 2022-9-27

[7]
Ferroptosis-Related Genes Are Potential Therapeutic Targets and the Model of These Genes Influences Overall Survival of NSCLC Patients.

Cells. 2022-7-15

[8]
Identification of a Novel Tumor Microenvironment Prognostic Signature for Bladder Urothelial Carcinoma.

Front Oncol. 2022-3-1

[9]
Ferroptosis Mediation Patterns Reveal Novel Tool to Implicate Immunotherapy and Multi-Omics Characteristics in Bladder Cancer.

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[10]
Novel Ferroptosis-Related Multigene Prognostic Models for Patients with Bladder Cancer.

Int J Gen Med. 2021-11-23

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