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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1419133
This article is part of the Research Topic Gastric Cancer: Individualized Immunotherapeutic Approaches and Biomarker-Driven Strategies View all 5 articles

Development and validation of a hypoxia- and mitochondrial dysfunction- related prognostic model based on integrated single-cell and bulk RNA sequencing analyses in gastric cancer

Provisionally accepted
Yirong Li Yirong Li Yue Cui Yue Cui Zhen Wang Zhen Wang Liwei Wang Liwei Wang Yi Yu Yi Yu *Yuyan Xiong Yuyan Xiong
  • Northwest University, Xi'an, China

The final, formatted version of the article will be published soon.

    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. In this study, the scRNA-seq and bulk RNA-seq data from stomach cancer cohorts were analyzed to identify HMDRGs. Five HMDRGs (ZFP36, SERPINE1, DUSP1, CAV1, and AKAP12) were identified by performing the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. A prognostic risk model was established to be able to stratify GC patients into high- and low-risk groups based on the median value of the risk scores. A nomogram model for predicting overall survival (OS) was developed, and it demonstrated consistent results with the actual observed OS. The ESTIMATE, CIBERSORT, and ssGSEA analyses were performed to evaluate immune infiltration, showing that individuals in the high-risk group tend to promote immune cell infiltration. Moreover, cancer immunotherapy evaluated by tumor immune dysfunction and exclusion (TIDE) and immunophenoscore (IPS) demonstrate that the 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.

    Keywords: gastric cancer, hypoxia, Mitochondrial dysfunction, prognosis, Model, Immunotherapy

    Received: 17 Apr 2024; Accepted: 22 Jul 2024.

    Copyright: © 2024 Li, Cui, Wang, Wang, Yu and Xiong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Yi Yu, Northwest University, Xi'an, 710075, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.