构建和评估食管鳞癌中与淋巴结转移相关的昼夜节律钟基因风险评分模型。
Construction and Evaluation of a Risk Score Model for Lymph Node Metastasis-Associated Circadian Clock Genes in Esophageal Squamous Carcinoma.
机构信息
Department of Cancer Center, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan 250033, China.
Department of Pharmacy, The Second Hospital of Shandong University, 247 Beiyuan Street, Jinan 250033, China.
出版信息
Cells. 2022 Oct 31;11(21):3432. doi: 10.3390/cells11213432.
BACKGROUND
Studies suggested that circadian clock genes (CCGs) in human esophageal squamous carcinoma (ESCC) samples are dysregulated. However, the relevance of CCGs to lymph node metastasis (LNM) and prognosis of ESCC remains unclear.
METHODS
The differentially expressed genes (DEGs) between normal and ESCC samples in The Cancer Genome Atlas database (TCGA) database were intersected with the genes associated with LNM (LNMGs) in ESCC samples and 300 CCGs to obtain the differentially expressed LNM-associated CCGs (DE-LNM-CCGs). The risk model was constructed by Cox regression analysis in the TCGA-ESCC training set, and the accuracy of the risk model was verified by risk profile and overall survival profile. Furthermore, differences of 23 immune cells, 13 immune functions, and immune checkpoint molecules between the high- and low-risk groups were assessed using the single-sample gene set enrichment analysis (ssGSEA) algorithm. Gene set enrichment analysis (GSEA) was conducted to investigate the functional differences between low- and high-risk groups. Finally, we validated the mRNA expression levels of prognostic model genes by quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
A total of six DE-LNM-CCGs were identified in TCGA-ESCC. TP53 and NAGLU were selected by Cox regression analysis to construct the risk model. Risk profile plots, overall survival plots, and validation results of the risk model in the validation set indicated that the constructed risk model was reliable. The result of ssGSEA showed that the percentages of activated B cells, activated dendritic cells, effector memory CD8 T cells, immune function in neutrophils, plasmacytoid dendritic cells, T cell co-inhibition, and Type 17 T helper cells were different between the high- and low-risk groups. In addition, the expression of CD274, PDCD1, TNFRSF18, and TNFRSF9 was dysregulated between the high- and low-risk groups. GSEA revealed that the high-risk group was associated with cell differentiation, oxidative phosphorylation, and steroid biosynthesis pathways, while the low-risk group was associated with chromosome, ECM-receptor interaction, and other pathways. Finally, qRT-PCR results showed that the mRNA expression levels of two prognostic genes were consistent with TCGA.
CONCLUSION
In conclusion, the risk model constructed based on TP53 and NAGLU could accurately predict the prognosis.
背景
研究表明，人类食管鳞状细胞癌（ESCC）样本中的生物钟基因（CCGs）失调。然而，CCGs 与 ESCC 的淋巴结转移（LNM）和预后的相关性尚不清楚。
方法
在癌症基因组图谱（TCGA）数据库中，将正常和 ESCC 样本之间的差异表达基因（DEGs）与 ESCC 样本中与 LNM 相关的基因（LNMGs）和 300 个 CCGs 进行交叉，获得差异表达的 LNM 相关 CCGs（DE-LNM-CCGs）。在 TCGA-ESCC 训练集中，通过 Cox 回归分析构建风险模型，并通过风险分布和总生存分布验证风险模型的准确性。此外，使用单样本基因集富集分析（ssGSEA）算法评估高、低风险组之间 23 种免疫细胞、13 种免疫功能和免疫检查点分子的差异。进行基因集富集分析（GSEA）以研究低、高风险组之间的功能差异。最后，通过实时定量聚合酶链反应（qRT-PCR）验证预后模型基因的 mRNA 表达水平。
结果
在 TCGA-ESCC 中确定了 6 个差异表达的 LNM-CCGs。通过 Cox 回归分析选择 TP53 和 NAGLU 构建风险模型。风险分布图谱、总生存图谱和验证集中风险模型的验证结果表明，构建的风险模型是可靠的。ssGSEA 的结果表明，高、低风险组之间激活的 B 细胞、激活的树突状细胞、效应记忆 CD8 T 细胞、中性粒细胞的免疫功能、浆细胞样树突状细胞、T 细胞共抑制和 17 型 T 辅助细胞的百分比不同。此外，高、低风险组之间 CD274、PDCD1、TNFRSF18 和 TNFRSF9 的表达失调。GSEA 显示，高危组与细胞分化、氧化磷酸化和类固醇生物合成途径相关，而低危组与染色体、ECM-受体相互作用和其他途径相关。最后，qRT-PCR 结果表明，两个预后基因的 mRNA 表达水平与 TCGA 一致。
结论
总之，基于 TP53 和 NAGLU 构建的风险模型可以准确预测预后。
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