基于胃癌的综合单细胞和大量RNA测序分析的缺氧和线粒体功能障碍与预后模型的开发和验证

胃癌（GC）仍然是全球主要的健康威胁，排名为第五大癌症。缺氧是实体瘤的特征，显着促进了GC的恶性进展。线粒体是低氧损伤的主要靶标，在包括GC在内的癌症发育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（HMDRG）的基因特征和预后模型尚未建立。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来构建预后模型。通过估计，Cibersort和SSGSEA分析评估免疫浸润。肿瘤免疫功能障碍和排除（TIDE）和免疫界（IPS）用于探索对免疫疗法的影响。此外，还进行了体外实验，以验证HMDRG在GC细胞恶性肿瘤中的功能作用。在这项研究中，鉴定了五个HMDRG（ZFP36，Serpine1，Dusp1，Cav1和Akap12），以在GC中开发预后模型。该模型根据中位风险评分将GC患者分为高风险组。构建了预测总生存期（OS）的列格图，并显示出观察到的OS的一致结果。免疫浸润分析表明，高危组的个体倾向于表现出增加的免疫细胞浸润。此外，对癌症免疫疗法反应的分析表明，与低风险组相比，高风险组患者对癌症免疫疗法的反应较差。免疫组织化学（IHC）染色表明，HMDRG的表达水平与GC显着相关，其中Serpine1表现出最明显的上调，而ZFP36在GC患者中表现出最著名的下调。此外，体外研究证实了Serpine1和ZFP36有助于与线粒体功能障碍相关的GC细胞的恶性过程。这项研究提出了一种新型和有效的方法来评估GC预后和免疫疗法的功效，并为理解GC的病原体提供洞察力。

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, in vitro 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.