Chen X, Liu HY, Zhou WB, Zhang LL, Huang J, Bao DW. Hypoxia-inducible factor 1-alpha and lactate dehydrogenase-A axis in metabolic changes and aggression in esophageal squamous-cell carcinoma. World J Gastrointest Oncol 2025; 17(3): 103450 [DOI: 10.4251/wjgo.v17.i3.103450]
Corresponding Author of This Article
Xia Chen, Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, No. 6 Beijing RD West, Huaiyin District, Huai’an 223300, Jiangsu Province, China. chenxia20222022@163.com
Research Domain of This Article
Cell Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Xia Chen, Hai-Yan Liu, Wu-Bi Zhou, Li-Li Zhang, Jian Huang, Da-Wei Bao, Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
Co-corresponding authors: Xia Chen and Hai-Yan Liu.
Author contributions: Chen X designed and supervised the study, performed the experiments and related analyses, and drafted the manuscript; Liu HY and Zhou WB performed bioinformatic analysis and manuscript writing; Zhang LL performed the experiments; Huan J and Bao DW writing-review and editing; all authors have read and approved the article. Chen X and Liu HY have significantly contributed to the research presented in this manuscript. Chen X was instrumental in designing and supervising the study, conducting experiments, performing related analyses, and drafting the manuscript. Liu HY carried out the bioinformatic analyses and contributed extensively to the writing of the manuscript. Given their substantial contributions to the conception, design, and execution of the research, as well as the drafting and revising of the manuscript, we propose that both Chen X and Liu HY be recognized as co-corresponding authors. This reflects their pivotal roles in guiding and shaping the study, ensuring the integrity and accuracy of the work presented. We appreciate the opportunity provided to disclose our research and welcome any feedback regarding this proposal.
Institutional review board statement: The studies involving human participants was approved by the Institutional Ethics Committee of Huaian Hospital of Huaian City (KY-2022-014-01).
Institutional animal care and use committee statement: As this research paper does not involve any animal experiments, it does not require the provision of an animal ethics approval or documentation.
Conflict-of-interest statement: The authors disclose no conflicts.
Data sharing statement: The datasets used and/or analyzed in the current study are available from the corresponding author upon reasonable request. The raw data of healthy and tumor human tissues were from GSE23400, GSE17351, GSE20347 in GEO database. The analysis code related to this study has been uploaded to the GitHub repository and is accessible at https: //github.com/ChenXia133/.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xia Chen, Department of Pathology, The Affiliated Huaian No. 1 People's Hospital of Nanjing Medical University, No. 6 Beijing RD West, Huaiyin District, Huai’an 223300, Jiangsu Province, China. chenxia20222022@163.com
Received: November 27, 2024 Revised: December 20, 2024 Accepted: January 14, 2025 Published online: March 15, 2025 Processing time: 84 Days and 0.6 Hours
Abstract
BACKGROUND
Esophageal squamous-cell carcinoma (ESCC) is a highly aggressive cancer, predominantly affecting populations in Eastern Asia and parts of Africa. Its pathogenesis is influenced by both genetic and environmental factors. Despite recent therapeutic advances, survival rates remain dismal, underscoring an urgent need for novel therapeutic targets.
AIM
To investigate the role of hypoxia-inducible factor 1-alpha (HIF1A) in the progression of ESCC and its impact on the metabolic enzyme lactate dehydrogenase A (LDHA), which is crucial for the glycolytic pathway in hypoxic tumor environments.
METHODS
Utilizing transcriptomic data from multiple public databases, we analyzed differential gene expression and conducted gene ontology and transcription factor network analyses. The regulatory impact of HIF1A on LDHA was specifically examined through integrative analysis with HIF1A ChIP-seq data and confirmed via siRNA-mediated knockdown experiments in ESCC cell lines.
RESULTS
Our findings reveal a significant upregulation of HIF1A in ESCC tissues, associated with poor prognosis. HIF1A directly regulates LDHA, enhancing glycolysis under hypoxic conditions and contributing to tumor aggressiveness. Knockdown of HIF1A in cell lines not only reduced LDHA expression but also altered key pathways related to cell cycle and apoptosis.
CONCLUSION
The critical role of the HIF1A-LDHA axis in ESCC highlights its potential as a therapeutic target, underscoring the need for future clinical trials to validate the efficacy of HIF1A inhibitors in enhancing treatment outcomes.
Core Tip: This study reveals that hypoxia-inducible factor 1-alpha (HIF1A) significantly influences the progression of esophageal squamous-cell carcinoma (ESCC) by regulating lactate dehydrogenase A (LDHA), which is crucial for glycolysis in hypoxic tumor environments. Our findings highlight the HIF1A-LDHA axis as a key contributor to metabolic reprogramming and tumor aggressiveness, presenting a potential target for therapeutic intervention. This insight could guide the development of HIF1A inhibitors to improve treatment outcomes in ESCC.
