Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China.
Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China.
PLoS One. 2023 Jul 5;18(7):e0288013. doi: 10.1371/journal.pone.0288013. eCollection 2023.
Previous studies have shown that the hypoxia microenvironment significantly impacted tumor progression. However, the clinical prognostic value of hypoxia-related risk signatures and their effects on the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains hazy. This study aimed to conduct novel hypoxia-related prognostic signatures and improve HCC prognosis and treatment.
Differentially expressed hypoxia-related genes (HGs) were identified with the gene set enrichment analysis (GSEA). Univariate Cox regression was utilized to generate the tumor hypoxia-related prognostic signature, which consists of 3 HGs, based on the least absolute shrinkage and selection operator (LASSO) algorithm. Then the risk score for each patient was performed. The prognostic signature's independent prognostic usefulness was confirmed, and systematic analyses were done on the relationships between the prognostic signature and immune cell infiltration, somatic cell mutation, medication sensitivity, and putative immunological checkpoints.
A prognostic risk model of four HGs (FDPS, SRM, and NDRG1) was constructed and validated in the training, testing, and validation datasets. To determine the model's performance in patients with HCC, Kaplan-Meier curves and time-dependent receiver operating characteristic (ROC) curves analysis was implemented. According to immune infiltration analysis, the high-risk group had a significant infiltration of CD4+ T cells, M0 macrophages, and dendritic cells (DCs) than those of the low-risk subtype. In addition, the presence of TP53 mutations in the high-risk group was higher, in which LY317615, PF-562271, Pyrimethamine, and Sunitinib were more sensitive. The CD86, LAIR1, and LGALS9 expression were upregulated in the high-risk subtype.
The hypoxia-related risk signature is a reliable predictive model for better clinical management of HCC patients and offers clinicians a holistic viewpoint when determining the diagnosis and course of HCC treatment.
先前的研究表明，缺氧微环境显著影响肿瘤的进展。然而，肝癌（HCC）中与缺氧相关的风险特征及其对肿瘤微环境（TME）的临床预后价值仍不明确。本研究旨在构建新的缺氧相关预后特征，并改善 HCC 的预后和治疗效果。
使用基因集富集分析（GSEA）鉴定差异表达的缺氧相关基因（HGs）。基于最小绝对收缩和选择算子（LASSO）算法，利用单因素 Cox 回归生成包含 3 个基因的肿瘤缺氧相关预后特征signature，然后对每位患者的风险评分进行计算。通过验证队列验证预后 signature 的独立预后价值，并对预后 signature 与免疫细胞浸润、体细胞突变、药物敏感性和潜在免疫检查点之间的关系进行系统分析。
构建并验证了包含 4 个基因（FDPS、SRM 和 NDRG1）的预后风险模型，该模型在训练、测试和验证数据集上均得到验证。为了确定该模型在 HCC 患者中的性能，我们进行了 Kaplan-Meier 曲线和时间依赖性 ROC 曲线分析。根据免疫浸润分析，高危组 CD4+T 细胞、M0 巨噬细胞和树突状细胞（DC）的浸润显著高于低危组。此外，高危组中 TP53 突变的发生率更高，LY317615、PF-562271、Pyrimethamine 和 Sunitinib 对高危组更敏感。高危组的 CD86、LAIR1 和 LGALS9 表达上调。
缺氧相关风险 signature 是预测 HCC 患者临床管理的可靠模型，为临床医生在确定 HCC 诊断和治疗方案时提供了全面的观点。
