Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, The Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China.
Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi, China.
Front Immunol. 2024 Aug 6;15:1419133. doi: 10.3389/fimmu.2024.1419133. eCollection 2024.
Gastric cancer (GC) remains a major global health threat ranking as the fifth most prevalent cancer. Hypoxia, a characteristic feature of solid tumors, significantly contributes to the malignant progression of GC. Mitochondria are the major target of hypoxic injury that promotes mitochondrial dysfunction during the development of cancers including GC. However, the gene signature and prognostic model based on hypoxia- and mitochondrial dysfunction-related genes (HMDRGs) in the prediction of GC prognosis have not yet been established.
The gene expression profile datasets of stomach cancer patients were retrieved from The Cancer Genome Atlas and the Gene Expression Omnibus databases. Prognostic genes were selected using Least Absolute Shrinkage and Selection Operator Cox (LASSO-Cox) regression analysis to construct a prognostic model. Immune infiltration was evaluated through ESTIMATE, CIBERSORT, and ssGSEA analyses. Tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) were utilized to explore implications for immunotherapy. Furthermore, in vitro experiments were conducted to validate the functional roles of HMDRGs in GC cell malignancy.
In this study, five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified for developing a prognostic model in GC. This model stratifies GC patients into high- and low-risk groups based on median risk scores. A nomogram predicting overall survival (OS) was constructed and showed consistent results with observed OS. Immune infiltration analysis indicated that individuals in the high-risk group tend to exhibit increased immune cell infiltration. Additionally, analysis of cancer immunotherapy responses revealed that high-risk group patients exhibit poorer responses to cancer immunotherapy compared to the low-risk group. Immunohistochemistry (IHC) staining indicated that the expression levels of HMDRGs were remarkably correlated with GC, of which, SERPINE1 displayed the most pronounced up-regulation, while ZFP36 exhibited the most notable down-regulation in GC patients. Furthermore, investigation validated that SERPINE1 and ZFP36 contribute to the malignant processes of GC cells correlated with mitochondrial dysfunction.
This study presents a novel and efficient approach to evaluate GC prognosis and immunotherapy efficacy, and also provides insights into understanding the pathogenesis of GC.
胃癌（GC）仍然是一个主要的全球健康威胁，位列第五大最常见癌症。缺氧是实体瘤的一个特征，它显著促进了 GC 的恶性进展。线粒体是缺氧损伤的主要靶点，在包括 GC 在内的癌症发展过程中促进线粒体功能障碍。然而，基于缺氧和线粒体功能障碍相关基因（HMDRGs）的基因特征和预后模型尚未在 GC 预后预测中建立。
从癌症基因组图谱和基因表达综合数据库中检索胃癌患者的基因表达谱数据集。使用最小绝对收缩和选择算子 Cox（LASSO-Cox）回归分析选择预后基因，构建预后模型。通过 ESTIMATE、CIBERSORT 和 ssGSEA 分析评估免疫浸润。利用肿瘤免疫功能障碍和排斥（TIDE）和免疫表型评分（IPS）探讨免疫治疗的意义。此外，进行体外实验验证 HMDRGs 在 GC 细胞恶性中的功能作用。
在这项研究中，确定了五个 HMDRGs（ZFP36、SERPINE1、DUSP1、CAV1 和 AKAP12）用于开发 GC 的预后模型。该模型基于中位数风险评分将 GC 患者分为高风险和低风险组。构建了一个预测总生存期（OS）的列线图，结果与观察到的 OS 一致。免疫浸润分析表明，高风险组个体倾向于表现出更高的免疫细胞浸润。此外，癌症免疫治疗反应分析表明，与低风险组相比，高风险组患者对癌症免疫治疗的反应较差。免疫组织化学（IHC）染色表明，HMDRGs 的表达水平与 GC 显著相关，其中 SERPINE1 的上调最为明显，而 ZFP36 在 GC 患者中的下调最为明显。此外，研究验证了 SERPINE1 和 ZFP36 与线粒体功能障碍相关，促进了 GC 细胞的恶性进程。
本研究提出了一种评估 GC 预后和免疫治疗疗效的新方法，为了解 GC 的发病机制提供了新的见解。
