Objectives: Hepatocellular carcinoma (HCC) patients at the same stage exhibit different prognosis, and the underlying molecular mechanism remains unclear. This study aims to identify the key genes impacting the prognosis of HCC patients.
Methods: Differentially expressed gene analyses were performed between HCC samples and normal ones, and between patients with long overall survival (OS) and those with short OS, in TCGA-LIHC and GSE14520 datasets. The Kaplan-Meier method with log-rank test was used to evaluate the role of secreted phosphoprotein 2 (SPP2) in the prognosis of HCC patients. Gene set enrichment analysis (GSEA) was used to understand the difference of enriched signaling pathways between SPP2-stratified HCC subgroups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to predict the potential functional pathways in which SPP2 might participate.
Results: SPP2 was significantly down-regulated in tumors when compared with normal tissues, or in tumor samples with short OS when compared with those with long OS [fold change (FC)>2 and false discovery rate (FDR)<0.05]. Low expression of SPP2 was associated with worse clinicopathological features like vascular invasion (P=1.6e-05), poor cancer status (with tumor, P=0.021), advanced T stage (T3 or T4, P=4.5e-04), advanced TNM stage (stage III or IV, P=3.1e-04), and with unfavorable prognosis (shorter OS, P=0.002). Gene enrichment analyses revealed that SPP2 might involve in the metabolic homeostasis of HCC and in the development of liver fibrosis and cirrhosis.
Conclusions: SPP2 might inhibit the development of liver fibrosis and cirrhosis and the tumorigenesis of HCC, and analogs of SPP2 might be potential drugs in the prevention of these diseases.
目的: 分期一致的肝细胞癌(hepatocellular carcinoma，HCC)患者其预后可能不同，其分子生物学机制仍不明确。本研究旨在鉴定影响肝癌预后的关键核心基因。方法: 在TCGA-LIHC和GSE14520数据集中，对HCC样本与正常样本、总生存期(overall survival，OS)长与OS短的患者进行差异表达基因分析。采用Kaplan-Meier法结合log-rank检验评价分泌型磷蛋白2(secreted phosphoprotein 2，SPP2)在HCC患者预后中的作用；基因集富集分析(gene set enrichment analysis，GSEA)了解SPP2分层的HCC亚组间富集信号通路的差异；基因本体论(Gene Ontology，GO)和京都基因与基因组数据库(Kyoto Encyclopedia of Genes and Genomes，KEGG)分析预测SPP2可能参与的信号分子通路。结果: 与正常组织相比，肿瘤组织中分泌的SPP2明显下调，且与长OS相比，短OS肿瘤样本中分泌的SPP2明显下调[表达倍数>2和伪发现率(false discovery rate，FDR)<0.05]。SPP2低表达与较差的临床病理特征相关，如血管侵犯(P=1.6e-05)、较差的肿瘤状态(合并肿瘤)(P=0.021)、较晚期的T期(T3或T4期)(P=4.5e-04)、较晚期的TNM期(III或IV期)(P=3.1e-04)、较差的预后(较短的生存期)(P=0.002)。基因富集分析表明SPP2可能参与了HCC的代谢稳态以及肝纤维化和肝硬化的发生、发展。结论: SPP2可能抑制肝纤维化和肝硬化的发展以及HCC的肿瘤发生，且SPP2类似物可能是预防肝硬化和肝细胞癌发生的潜在药物。.
目的: 分期一致的肝细胞癌(hepatocellular carcinoma，HCC)患者其预后可能不同，其分子生物学机制仍不明确。本研究旨在鉴定影响肝癌预后的关键核心基因。
方法: 在TCGA-LIHC和GSE14520数据集中，对HCC样本与正常样本、总生存期(overall survival，OS)长与OS短的患者进行差异表达基因分析。采用Kaplan-Meier法结合log-rank检验评价分泌型磷蛋白2(secreted phosphoprotein 2，SPP2)在HCC患者预后中的作用；基因集富集分析(gene set enrichment analysis，GSEA)了解SPP2分层的HCC亚组间富集信号通路的差异；基因本体论(Gene Ontology，GO)和京都基因与基因组数据库(Kyoto Encyclopedia of Genes and Genomes，KEGG)分析预测SPP2可能参与的信号分子通路。
结果: 与正常组织相比，肿瘤组织中分泌的SPP2明显下调，且与长OS相比，短OS肿瘤样本中分泌的SPP2明显下调[表达倍数>2和伪发现率(false discovery rate，FDR)<0.05]。SPP2低表达与较差的临床病理特征相关，如血管侵犯(P=1.6e-05)、较差的肿瘤状态(合并肿瘤)(P=0.021)、较晚期的T期(T3或T4期)(P=4.5e-04)、较晚期的TNM期(III或IV期)(P=3.1e-04)、较差的预后(较短的生存期)(P=0.002)。基因富集分析表明SPP2可能参与了HCC的代谢稳态以及肝纤维化和肝硬化的发生、发展。
结论: SPP2可能抑制肝纤维化和肝硬化的发展以及HCC的肿瘤发生，且SPP2类似物可能是预防肝硬化和肝细胞癌发生的潜在药物。
Keywords: gene set enrichment analysis; hepatocellular carcinoma; secreted phosphoprotein 2; tumorigenesis.