Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Aug 15, 2025; 17(8): 106781
Published online Aug 15, 2025. doi: 10.4251/wjgo.v17.i8.106781
GEN1 regulates cell proliferation, migration, apoptosis and ferroptosis in gastric cancer
Qi Zhang, Zu-Guo Yuan, Kai-Feng Zheng, Ke Chen
Qi Zhang, Department of Gastroenterology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China
Zu-Guo Yuan, Kai-Feng Zheng, Ke Chen, Chemoradiotherapy Center of Oncology, The Affiliated People’s Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China
Author contributions: Zhang Q contributed to conception and design, analysis and interpretation, critical revision of the article and final approval of the article; Yuan ZG contributed to data collection; Zheng KF and Chen K contributed to writing the article; All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Institutional review board statement: This study was approved by the ethics committee of The Affiliated People’s Hospital of Ningbo University (No. 2023010901).
Institutional animal care and use committee statement: This study does not involve any animal experiments.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: No additional data are available.
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: Qi Zhang, MD, Doctor, Department of Gastroenterology, The Affiliated People’s Hospital of Ningbo University, No. 251 Baizhang East Road, Ningbo 315000, Zhejiang Province, China. matin219@163.com
Received: April 8, 2025
Revised: May 8, 2025
Accepted: June 20, 2025
Published online: August 15, 2025
Processing time: 127 Days and 15.3 Hours
Abstract
BACKGROUND

Gastric cancer (GC) has a high prevalence and mortality overall. GEN1 is associated with abnormal centrosome amplification, DNA damage and increased apoptosis. To date, little is known about the function and mechanism of GEN1 in GC.

AIM

To explore the cellular processes associated with GC will help to elucidate the mechanism of the occurrence and development of GC and discover potential therapeutic targets.

METHODS

The detection of GEN1 expression at mRNA and protein levels was done by real-time quantitative polymerase chain reaction and western blotting. The function of GEN1 was verified by loss-of-function experiments in AGS cells. The genes co-expressed with GEN1 were searched from the stomach adenocarcinomas (STAD) data in The Cancer Genome Atlas database. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the genes co-expressed with GEN1 to further identify the pathways involved in GEN1. Rescue experiments using ferroptosis inhibitor ferrostatin-1 and chemotherapeutic sensitivity assays with cisplatin were also performed.

RESULTS

Significant up-regulation of GEN1 was observed in GC cell lines AGS and MGC-803. Inhibition of GEN1 induced cell apoptosis and decreased cell proliferation, cycle progression, migration in AGS cells. There were 264 genes co-expressed with GEN1 in STAD cohort (r > 0.4, P < 0.001). KEGG enrichment analysis showed that GEN1 might be associated with the cell cycle, Fanconi anemia pathway, homologous recombination, oocyte meiosis and cellular senescence in GC. Furthermore, CCNA2, CCNB1, CCNB2, cyclin-dependent kinase (CDK) 1, CDK2 and polo-like kinase 1 protein levels were lower in GEN1-knockdown AGS cells, manifesting that GEN1 was associated with the cell cycle pathway in AGS cells. Downregulation of GEN1 decreased adenosine triphosphate content and elevated reactive oxygen species in AGS cells, suggesting that GEN1 silencing led to mitochondrial dysfunction in AGS cells. In addition, GEN1 silencing caused an overt decrease in FTH1 and GPX4 protein levels and a significant elevation in ACSL4 protein levels, implying that GEN1 silencing promoted AGS cell ferroptosis. Treatment with ferrostatin-1 rescued cell viability loss induced by GEN1 knockdown, confirming ferroptosis as a key death mechanism. Additionally, GEN1-deficient AGS cells showed enhanced sensitivity to cisplatin, with a significantly reduced half-maximal inhibitory concentration compared to control cells.

CONCLUSION

GEN1 promotes GC cell proliferation and migration while suppressing apoptosis and ferroptosis. Targeting GEN1 not only disrupts mitochondrial function and cell cycle progression but also sensitizes GC cells to ferroptosis and chemotherapy. These findings highlight GEN1 as a potential therapeutic target for enhancing treatment efficacy in gastric cancer.

Keywords: Gastric cancer; GEN1; Cell cycle; Ferroptosis; The Cancer Genome Atlas database

Core Tip: GEN1 promotes gastric cancer (GC) cell proliferation and migration while suppressing apoptosis and ferroptosis. Targeting GEN1 not only disrupts mitochondrial function and cell cycle progression but also sensitizes GC cells to ferroptosis and chemotherapy. These findings highlight GEN1 as a potential therapeutic target for enhancing treatment efficacy in GC.