IRF1 suppresses gastric tumorigenesis via dual PI3K/AKT-ERK pathway modulation and functional antagonism of oncogenic MX2

Sep 23, 2026

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Interferon regulatory factor 1 (IRF1) is central to the type I interferon response, yet its functional role and mechanism in gastric cancer remain unclear. This study evaluates IRF1’s contribution to gastric cancer progression and assesses therapeutic potential. IRF1 expression is profiled using TCGA and GTEx, verified in 366 patients by immunohistochemistry, then tested through cell and xenograft functional assays alongside molecular interaction analyses focusing on MX2 and PI3K/AKT-ERK signaling.

LanguageEnglish

CategoryResearch & Report

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Pages19

Reading Time48 min

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Abstract

Background

Methods

Results

Conclusions

Background

Interferons and interferon signaling

Cellular Oncology (2026) 49:24 [https://doi.org/10.1007/s13402-025-01](https://doi.org/10.1007/s13402-025-01)134-w RESEARCH IRF1 suppresses gastric tumorigenesis via dual PI3K/AKT-ERK pathway modulation and functional antagonism of oncogenic MX2 Wenjing Chen1 · Neng Lou2 · Xietao Chen1 · Xianjing Hu3 · Chenchen Mao2 · Jiaqi Yang2 · Jun Cheng1 · Chenbin Chen1 · Xiangyang Xue2,5 · Xian Shen1,4 Received: 12 April 2025 / Accepted: 27 November 2025 © The Author(s) 2025 Abstract Background Interferon regulatory factor 1 (IRF1) plays a crucial role in the type I interferon (IFN) response. However, its functional role and underlying mechanisms in gastric cancer (GC) remain unclear. This study aims to investigate the biological significance ofIRF1 in GC progression and its potential as a therapeutic target. Methods IRF1 expression was analyzed using The Cancer Genome Atlas (TCGA) and GTEx databases, validated by immunohistochemistry (IHC) in 366 GC patients. Functional experiments, including CCK-8, Transwell migration and invasion assays, and apoptosis analysis, were conducted in GC cell lines with IRF1 overexpression or knockdown. A subcutaneous xenograft model was established to evaluate the in vivo effects ofIRF1 on tumor growth. Co-immunoprecipitation and western blotting were performed to explore the molecular interactions between IRF1 and Myxovirus resistance 2 (MX2), as well as its regulation of the PI3K signaling pathway. Results IRF1 expression was significantly higher in gastric cancer tissues than in adjacent normal tissues. Higher IRF1 levels were also associated with improved patient survival. Overexpression of IRF1 inhibited GC cell proliferation, migration, and invasion while promoting apoptosis, whereas IRF1 knockdown had the opposite effects. Mechanistically, IRF1 suppressed PI3K/p-AKT signaling while enhancing p-ERK1/2 activation. Moreover, IRF1 directly interacted with MX2, a protein involved in epithelial-mesenchymal transition (EMT), and this interaction was essential for suppressing MX2-mediated oncogenic activity. In vivo experiments confirmed that IRF1 overexpression significantly reduced tumor growth and metastasis. Conclusions IRF1 functions as a tumor suppressor in GC by modulating the PI3K signaling pathway and interacting with MX2 to inhibit EMT. These findings highlight IRF1 as a potential therapeutic target for GC treatment. Keywords IRF1 · Gastric cancer · Type i interferon response · PI3K signaling · MX2 · EMT · Tumor suppression Wenjing Chen, Neng Lou and Xietao Chen contributed equally to this work. 􀀍 Xiangyang Xue [wzxxy@wmu.edu.cn](wzxxy@wmu.edu.cn) 􀀍 Xian Shen [13968888872@163.com](13968888872@163.com) 1 Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China 2 Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, Wenzhou Medical University, Wenzhou, China 3 Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital, Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 4 Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China 5 Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Zhejiang International Cooperation Base for Tumor-Associated Pathogen and Host Interaction, Institute of Molecular Virology and Immunology, Department of Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Zhejiang,Wenzhou, China 1 3 1 Background Cancer remains a leading cause of mortality worldwide, treatment outcomes for many solid tumors remain unsatisfactory. The shift toward precision oncology has improved outcomes in select cancers, but challenges such as tumor heterogeneity, immune evasion, and therapeutic resistance persist [1]. Gastric cancer (GC

FAQs

How was IRF1 expression evaluated in gastric cancer samples?

IRF1 expression was analyzed using TCGA and GTEx databases and validated by immunohistochemistry in 366 gastric cancer patients.

What cellular and in vivo effects did IRF1 have on gastric cancer progression?

IRF1 overexpression inhibited proliferation, migration, and invasion while promoting apoptosis; knockdown produced opposite effects. Xenograft experiments showed IRF1 overexpression reduced tumor growth and metastasis.

Which molecular mechanisms link IRF1 to tumor suppression?

IRF1 suppressed PI3K/p-AKT signaling and enhanced p-ERK1/2 activation. IRF1 directly interacted with MX2, and this interaction was required to suppress MX2-driven oncogenic activity and EMT.

Sep 23, 2026

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