基于天冬酰胺代谢的分类揭示了肝细胞癌的代谢和免疫异质性。
An asparagine metabolism-based classification reveals the metabolic and immune heterogeneity of hepatocellular carcinoma.
机构信息
Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
出版信息
BMC Med Genomics. 2022 Oct 25;15(1):222. doi: 10.1186/s12920-022-01380-z.
INTRODUCTION AND OBJECTIVES
hepatocellular carcinoma (HCC) is the major form of liver cancer with a poor prognosis. Amino acid metabolism has been found to alter in cancers and contributes to malignant progression. However, the asparagine metabolism status and relevant mechanism in HCC were barely understood.
METHODS
By conducting consensus clustering and the least absolute shrinkage and selection operator regression of HCC samples from three cohorts, we classified the HCC patients into two subtypes based on asparagine metabolism level. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analyses and Gene Set Enrichment Analysis of the differentially expressed genes between two subgroups were conducted. Immune cell infiltration was evaluated using CIBERSORT algorithm. The prognostic values of genes were analyzed by univariate and multivariate cox regression, ROC curve and Kaplan-Meier survival estimate analyses. Cell types of sing-cell RNA sequencing (scRNA-seq) data were clustered utilizing UMAP method.
RESULTS
HCC patients with higher asparagine metabolism level have worse prognoses. Moreover, we found the distinct energy metabolism patterns, DNA damage response (DDR) pathway activating levels, drug sensitivities to DDR inhibitors, immune cell compositions in the tumor microenvironment and responses to immune therapy between two subgroups. Further, we identified a potential target gene, glutamic-oxaloacetic transaminase 2 (GOT2). GOT2 downregulation was associated with worse HCC prognosis and increased infiltration of T regulatory cells (Tregs). ScRNA-seq revealed the GOT2 downregulation in cancer stem cells compared with HCC cells.
CONCLUSIONS
Taken together, HCC subtype which is more reliant on asparagine and glutamine metabolism has a worse prognosis, and a core gene of asparagine metabolism GOT2 is a potential prognostic marker and therapeutic target of HCC. Our study promotes the precision therapy of HCC and may improve patient outcomes.
简介和目的
肝细胞癌（HCC）是肝癌的主要形式，预后不良。已发现氨基酸代谢在癌症中发生改变，并有助于恶性进展。然而，HCC 中天冬酰胺代谢状态及其相关机制仍知之甚少。
方法
通过对来自三个队列的 HCC 样本进行共识聚类和最小绝对收缩和选择算子回归，我们根据天冬酰胺代谢水平将 HCC 患者分为两种亚型。对两个亚组之间差异表达基因进行基因本体论、京都基因与基因组百科全书分析和基因集富集分析。使用 CIBERSORT 算法评估免疫细胞浸润。通过单因素和多因素 cox 回归、ROC 曲线和 Kaplan-Meier 生存估计分析评估基因的预后价值。使用 UMAP 方法对单细胞 RNA 测序（scRNA-seq）数据的细胞类型进行聚类。
结果
天冬酰胺代谢水平较高的 HCC 患者预后较差。此外，我们发现两个亚组之间存在明显的能量代谢模式、DNA 损伤反应（DDR）途径激活水平、DDR 抑制剂的药物敏感性、肿瘤微环境中的免疫细胞组成以及对免疫治疗的反应不同。此外，我们鉴定出一个潜在的靶基因，即谷草转氨酶 2（GOT2）。GOT2 下调与 HCC 预后较差和 T 调节细胞（Tregs）浸润增加有关。scRNA-seq 显示 GOT2 在癌症干细胞中较 HCC 细胞下调。
结论
综上所述，更依赖天冬酰胺和谷氨酸代谢的 HCC 亚型预后较差，天冬酰胺代谢的核心基因 GOT2 是 HCC 的潜在预后标志物和治疗靶点。我们的研究促进了 HCC 的精准治疗，并可能改善患者的预后。
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