Basic Study
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World J Gastrointest Oncol. Jun 15, 2025; 17(6): 105213
Published online Jun 15, 2025. doi: 10.4251/wjgo.v17.i6.105213
Endothelial Per-Arnt-Sim domain-containing protein 1 expression is correlated with poor prognosis and promotes invasion and metastasis in gastric cancer
Wang Xu, Wang Li, Jia Ru
Wang Xu, Wang Li, Department of Emergency, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
Jia Ru, Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
Co-first authors: Wang Xu and Wang Li.
Author contributions: Xu W designed the research study, writing-original drafted the manuscript; Li W designed the project, methodology and funding acquisition; made the original figure and tables; Ru J designed the study, supervised the data collection, writing-review and edited the manuscript. All authors contributed to the critical revision of the paper and approved the final manuscript for publication. All authors contributed to the critical revision of the paper and approved the final manuscript for publication. Xu W and Li W contributed equally to this work as co-first authors.
Institutional review board statement: This study was approved by the Ethics Committee of The Second Affiliated Hospital of Zhejiang University School of Medicine (2023-0177). All patients gave written informed consent for the donation of their tissue for the current study prior to surgery, in accordance with the World Medical Association's ethics guidelines (Declaration of Helsinki). The requirement for informed consent from the patients was waived owing to the retrospective nature of the investigation.
Institutional animal care and use committee statement: All Animal experiments procedures followed the ethical guidelines established by the Animal Protection and Use Committee of Zhejiang University of Traditional Chinese Medicine and were approved (IACUC-20220314-05).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data underlying this article are available in the article. If needed, please contact with the corresponding author.
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: Jia Ru, Senior Researcher, Department of Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang Road, Hangzhou 310000, Zhejiang Province, China. 2520089@zju.edu.cn
Received: January 15, 2025
Revised: April 19, 2025
Accepted: May 13, 2025
Published online: June 15, 2025
Processing time: 150 Days and 5.6 Hours
Abstract
BACKGROUND

Gastric cancer (GC) is a leading cause of cancer-related death worldwide. Hypoxia, which is common in solid tumors, contributes to tumor progression. EPAS1, also known as HIF2-α, is a key regulator of cellular responses to hypoxia and is implicated in carcinogenesis. While less studied than HIF1-α is, EPAS1 is overexpressed in various cancers, including GC.

AIM

To assess the relationship between EPAS1 expression and prognosis in GC and investigate its possible role in the development of GC.

METHODS

EPAS1 expression in GC and adjacent tissues was assessed using immunohistochemistry. Correlations with clinicopathological features were analyzed by using The Cancer Genome Atlas (TCGA) and clinical data to evaluate its prognostic value. The TIMER2.0 database was used to examine associations between EPAS1 and immune-infiltrating cells. Gene set enrichment analysis identified the mechanisms underlying the role of EPAS1 in GC progression. The relationships between EPAS1 and immunological checkpoints were analyzed in the TCGA-STAD cohort. Cell and animal experiments confirmed the role of EPAS1 in invasion and metastasis.

RESULTS

EPAS1 expression was significantly greater in GC tissues than in adjacent tissues (P < 0.05). High EPAS1 expression was correlated with shorter overall survival (OS) and was associated with greater infiltration depth and poorer tumor differentiation (P < 0.05). Univariate and multivariate Cox analyses revealed that EPAS1 expression (HR: 2.095; 95%CI: 1.019-4.307; P < 0.001) was an independent predictor of OS. EPAS1 was enriched in the epithelial-mesenchymal transition (EMT), inflammatory response, KRAS, TGF-β, TNF-/NF-kB, and IL6/JAK/STAT3 signaling pathways. The high EPAS1 expression group presented increased levels of pathway-related molecules and immunotherapy checkpoints. In vitro and in vivo studies confirmed that silencing EPAS1 reduced GC cell invasion and metastasis.

CONCLUSION

EPAS1 may be a prognostic marker in patients with GC and may promote tumor growth through the immune response and pathways associated with EMT, inflammatory response, KRAS, TGF-β, TNF-/NF-kB, and IL6/JAK/STAT3 signaling.

Keywords: Endothelial Per-Arnt-Sim domain-containing protein 1; Gastric cancer; Survival curve analysis; Immune checkpoint; Bioinformatics analysis

Core Tip: EPAS1 expression is significantly higher in gastric cancer (GC) tissues than in adjacent tissues and is correlated with poor overall survival in patients with GC. High EPAS1 expression is associated with increased infiltration, poor tumor differentiation, and the activation of multiple signaling pathways, including the epithelial-mesenchymal transition, inflammatory response, KRAS, TGF-β, TNF-/NF-kB, and IL6/JAK/STAT3 pathways. EPAS1 also enhances the invasion and metastasis of GC cells. These findings suggest that EPAS1 may serve as an independent prognostic marker and contribute to tumor progression through immune responses and key signaling pathways.