基于TCGA数据库分析PFKFB4在肝细胞癌的临床意义及分子机制

Analysis of the clinical significance and molecular mechanism of PFKFB4 in hepatocellular carcinoma based on the TCGA database

目的研究6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶4(PFKFB4)在肝细胞肝癌(LIHC)中表达和甲基化与预后的关系,分析PFKFB4在LIHC恶性进展中的作用机制。方法从TCGA数据库下载LIHC的RNA-seq数据和临床信息,分析比较PFKFB4在LIHC样本和正常样本中的表达差异,利用卡方检验分析PFKFB4与患者临床特征的关系。通过Kaplan-Meier法和Cox风险回归分析PFKFB4在LIHC中的预后价值。利用基因富集分析(GSEA)探索PFKFB4参与的分子通路,并通过MethSurv和TCGA Wanderer等在线数据库分析PFKFB4与LIHC发展有关的甲基化位点。结果PFKFB4在LIHC样本中的表达水平显著上调,差异有统计学意义(P<0.05),其表达与患者的Stage分期呈显著负相关(P<0.05),PFKFB4高表达组的患者总体生存率(OS)比低表达组更差(P<0.05),可作为LIHC的独立预后因子(HR=1.908,95%CI:1.332~2.733,P<0.05)。GSEA分析结果提示,PFKFB4可能参与糖酵解、细胞自噬和P53等信号通路,并通过PFKFB4的去甲基化调控PFKFB4的表达,影响预后。结论PFKFB4的低甲基化水平使PFKFB4在LIHC中显著上调,可通过多条分子通路调控LIHC的发生发展,是LIHC的独立预后因子。

Objective To study the relationship between the expression and methylation of fructose-6-phosphate-2-kinase/fructose-2-diphosphatase 4(PFKFB4)in liver hepatocellular carcinoma(LIHC)and prognosis,and analyze the mechanism of PFKFB4 in the malignant progression of LIHC.Methods Download RNA-seq data and the clinical information of LIHC from the TCGA database,and the expression levels of PFKFB4 in LIHC tissue and normal tissue were analyzed and compared.Chi-square test was used to analyze the relationship between PFKFB4 and the clinical characteristics of patients.The Kaplan-Meier method and Cox risk regression was used to analyze the prognostic value of PFKFB4 in LIHC.Gene enrichment analysis(GSEA)was used to explore the molecular pathways that PFKFB4 involved,and then online analysis of MethSurv and TCGA Wanderer database was used to find the methylation sites related to the development of LIHC.Results The expression of PFKFB4 in LIHC samples was significantly up-regulated(P<0.05),and its expression was significantly negative correlated with stage of patients(P<0.05).The overall survival rate(OS)of patients in the high expression group of PFKFB4 was worse than that in the low expression group(P<0.05),which can be used as an independent prognostic factor of LIHC(HR=1.908,95%CI:1.332~2.733,P<0.05).GSEA analysis results suggest that PFKFB4 may be involved in glycolysis,autophagy and P53 signaling pathways,and regulate the expression of PFKFB4 through the demethylation of PFKFB4,and affect the prognosis.Conclusion The hypomethylation level of PFKFB4 significantly upregulates PFKFB4 in LIHC,which can regulate the occurrence and development of LIHC through multiple molecular pathways,andis an independent prognostic factor of LIHC.