背景:全球肝癌发病率排名第六,死亡率排名第三,肝细胞癌(HCC)占其90%。缺氧,糖酵解,和乳酸代谢已被发现分别调节肝癌的进展。然而,缺乏将上述三者联系起来预测HCC预后的研究。本研究旨在确定缺氧-糖酵解-乳酸相关的基因特征,以评估HCC的预后。
方法:本研究从分子特征数据库(MSigDB)收集了510个缺氧-糖酵解-乳酸基因,然后通过分析缺氧-糖酵解-乳酸基因表达对TCGA-LIHC的HCC患者进行分类。通过LASSO-Cox分析筛选出差异表达基因(DEGs)以构建基因标签。使用单变量和多变量回归分析来评估基因标签的独立预后价值。免疫浸润分析,体细胞突变,和相关热图由“GSVA”R包进行。由“SingleR”进行的单细胞分析,\"celldex\",\"Seurat\",和“CellCha”R包揭示了签名基因如何参与缺氧/糖酵解/乳酸代谢和PPI网络识别的枢纽基因。
结果:我们将来自TCGA-LIHC的HCC患者分为两组,并筛选出DEGs。18个基因的预后特征,包括CDCA8,CBX2,PDE6A,MED8,DYNC1LI1,PSMD1,EIF5B,GNL2,SEPHS1,CCNJL,SOCS2,LDHA,G6PD,YBX1,RTN3,ADAMTS5,CLEC3B,建立UCK2以分层HCC的风险。缺氧-糖酵解-乳酸基因标记的风险评分被进一步确定为评估HCC预后的有价值的独立因素。然后我们发现临床特征,免疫浸润,体细胞突变,相关分析在高危组和低危组之间存在差异。此外,单细胞分析表明,标记基因可以与肝细胞/成纤维细胞/浆细胞的配体受体相互作用,参与缺氧/糖酵解/乳酸代谢,PPI网络确定了该过程中的潜在枢纽基因:CDCA8,LDHA,YBX1。
结论:我们构建的缺氧-糖酵解-乳酸相关基因标签可以为HCC提供预后价值,并为未来的HCC研究提供几个中心基因。
BACKGROUND: Liver cancer ranks sixth in incidence and third in mortality globally and hepatocellular carcinoma (HCC) accounts for 90% of it. Hypoxia, glycolysis, and lactate metabolism have been found to regulate the progression of HCC separately. However, there is a lack of studies linking the above three to predict the prognosis of HCC. The present study aimed to identify a hypoxia-glycolysis-lactate-related gene signature for assessing the prognosis of HCC.
METHODS: This study collected 510 hypoxia-glycolysis-lactate genes from Molecular Signatures Database (MSigDB) and then classified HCC patients from TCGA-LIHC by analyzing their hypoxia-glycolysis-lactate genes expression. Differentially expressed genes (DEGs) were screened out to construct a gene signature by LASSO-Cox analysis. Univariate and multivariate regression analyses were used to evaluate the independent prognostic value of the gene signature. Analyses of immune infiltration, somatic cell mutations, and correlation heatmap were conducted by \"GSVA\" R package. Single-cell analysis conducted by \"SingleR\", \"celldex\", \"Seurat\", and \"CellCha\" R packages revealed how signature genes participated in hypoxia/glycolysis/lactate metabolism and PPI network identified hub genes.
RESULTS: We classified HCC patients from TCGA-LIHC into two clusters and screened out DEGs. An 18-genes prognostic signature including CDCA8, CBX2, PDE6A, MED8, DYNC1LI1, PSMD1, EIF5B, GNL2, SEPHS1, CCNJL, SOCS2, LDHA, G6PD, YBX1, RTN3, ADAMTS5, CLEC3B, and UCK2 was built to stratify the risk of HCC. The risk score of the hypoxia-glycolysis-lactate gene signature was further identified as a valuable independent factor for estimating the prognosis of HCC. Then we found that the features of clinical characteristics, immune infiltration, somatic cell mutations, and correlation analysis differed between the high-risk and low-risk groups. Furthermore, single-cell analysis indicated that the signature genes could interact with the ligand-receptors of hepatocytes/fibroblasts/plasma cells to participate in hypoxia/glycolysis/lactate metabolism and PPI network identified potential hub genes in this process: CDCA8, LDHA, YBX1.
CONCLUSIONS: The hypoxia-glycolysis-lactate-related gene signature we built could provide prognostic value for HCC and suggest several hub genes for future HCC studies.