A glycolysis-based 4-mRNA signature correlates with the prognosis and cell cycle process in patients with bladder cancer
A glycolysis-based 4-mRNA signature correlates with the prognosis and cell cycle process in patients with bladder cancer
复制标题
基于糖酵解的 4-mRNA 特征与膀胱癌患者的预后和细胞周期过程相关
DOI：
10.1186/s12935-020-01255-2
复制
发表时间：
2020-05-20
影响因子：
5.8
通讯作者：
Yin, Hubin
中科院分区：
文献类型：
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作者：
Zhang, Chen;Gou, Xin;Yin, Hubin
膀胱癌是世界范围内最常见的恶性肿瘤之一。然而，传统指标对膀胱癌临床预后的预测作用有限。本研究的目的是开发和验证糖酵解相关基因标志，以预测治疗选择有限的膀胱癌患者的预后。方法从癌症基因组图谱(TCGA)数据库中获得膀胱癌患者的smRNA表达谱。基因集浓缩分析(GSEA)用于确定膀胱癌组织和配对正常组织中显著不同的糖酵解基因集。通过单因素和多因素COX分析，构建预后相关基因特征图。使用Kaplan-Meier曲线和随时间变化的接收器工作特性(ROC)曲线来评估签名。构建了结合基因特征和临床参数的诺模图。分析糖酵解相关基因特征与分子特征和癌症亚型的相关性。用RT-qPCR法分析基因表达。结果COX比例回归模型显示，4-mR NA信号(NUP205、NUPL2、PFKFB1和PKM)与膀胱癌患者的预后显著相关。根据签名，患者被分为高风险组和低风险组，具有不同的预后结果。基因标记是总存活率的独立预后指标。在另外两个验证数据集中测试了4-信使核糖核酸标记作出准确预测的能力。GSEA分析细胞周期、缺氧、P53通路、PI3K/AKT/mTOR通路等与4-mRNA相关的典型通路和生物学过程。生成了一个热图，显示了风险分数和细胞周期特征之间的相关性。RT-qPCR揭示了在正常组织和癌组织中差异表达的基因。实验表明，PKM2在细胞增殖和细胞周期中起着至关重要的作用。结论所建立的4-mRNA信号可作为膀胱癌患者准确预测预后的模型，但其具体的生物学机制有待进一步验证。
BackgroundBladder cancer is one of the most prevalent malignancies worldwide. However, traditional indicators have limited predictive effects on the clinical outcomes of bladder cancer. The aim of this study was to develop and validate a glycolysis-related gene signature for predicting the prognosis of patients with bladder cancer that have limited therapeutic options.MethodsmRNA expression profiling was obtained from patients with bladder cancer from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was conducted to identify glycolytic gene sets that were significantly different between bladder cancer tissues and paired normal tissues. A prognosis-related gene signature was constructed by univariate and multivariate Cox analysis. Kaplan–Meier curves and time-dependent receiver operating characteristic (ROC) curves were utilized to evaluate the signature. A nomogram combined with the gene signature and clinical parameters was constructed. Correlations between glycolysis-related gene signature and molecular characterization as well as cancer subtypes were analyzed. RT-qPCR was applied to analyze gene expression. Functional experiments were performed to determine the role of PKM2 in the proliferation of bladder cancer cells.ResultsUsing a Cox proportional regression model, we established that a 4-mRNA signature (NUP205, NUPL2, PFKFB1 and PKM) was significantly associated with prognosis in bladder cancer patients. Based on the signature, patients were split into high and low risk groups, with different prognostic outcomes. The gene signature was an independent prognostic indicator for overall survival. The ability of the 4-mRNA signature to make an accurate prognosis was tested in two other validation datasets. GSEA was performed to explore the 4-mRNA related canonical pathways and biological processes, such as the cell cycle, hypoxia, p53 pathway, and PI3K/AKT/mTOR pathway. A heatmap showing the correlation between risk score and cell cycle signature was generated. RT-qPCR revealed the genes that were differentially expressed between normal and cancer tissues. Experiments showed that PKM2 plays essential roles in cell proliferation and the cell cycle.ConclusionThe established 4‑mRNA signature may act as a promising model for generating accurate prognoses for patients with bladder cancer, but the specific biological mechanism needs further verification.