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Cellular and Molecular Biology

VASN drives gastric tumorigenesis via activation of the COL4A1/PI3K/AKT axis during Helicobacter pylori infection

British Journal of Cancer (2025)Cite this article

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Abstract

Background

Vasorin (VASN) is linked to tumor progression in various cancers, its role and regulatory mechanisms in gastric cancer (GC) are still unknown.

Methods

Human gastric mucosal samples, VASN heterozygous-deficient (VASN+/-) C57BL/6 mice, and gastric cell lines with VASN knockdown and overexpression were used to study VASN’s role in GC. A combination of in vitro and in vivo models, RNA sequencing (RNA-seq), proteomics, bioinformatics, and various assays revealed VASN’s critical involvement in GC.

Results

Elevated VASN expression was significantly associated with poor clinical outcomes in GC patients. We identified a strong correlation between increased VASN expression, driven by Helicobacter pylori (H. pylori) infection, and the progression of gastric carcinogenesis. Functional studies demonstrated that VASN overexpression enhanced the proliferation, migration, and invasion of gastric epithelial cells, whereas VASN knockdown suppressed these malignant phenotypes. Mechanistically, the collagen type IV alpha 1 chain (COL4A1) was identified as a critical downstream effector of VASN in GC. VASN exerted its oncogenic effects by regulating COL4A1 to activate the PI3K/AKT signaling pathway. Furthermore, H. pylori infection was demonstrated to induce hypoxia-inducible factor-1 alpha (HIF-1α) expression, which subsequently upregulated VASN.

Conclusions

The HIF-1α-VASN-COL4A1-PI3K/AKT signaling pathway is crucial for gastric tumor development and may represent a therapeutic target for GC.

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Fig. 1: High levels of VASN are found in gastric cancer (GC) tissues, which correlates with a negative prognosis.
Fig. 2: VASN contributes to the proliferation, migration, and invasion of gastric epithelial cells.
Fig. 3: Identification of COL4A1 as a potential downstream target of VASN.
Fig. 4: Cell proliferation, migration, and invasion are promoted by VASN through the regulation of COL4A1.
Fig. 5: VASN activates the PI3K/AKT signaling pathway via COL4A1.
Fig. 6: VASN is involved in H. pylori-induced gastric carcinogenesis.
Fig. 7: VASN expression is elevated by HIF-1α in the context of gastric carcinogenesis triggered by H. pylori.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Support for this work came from the Key Laboratory Project of Digestive Diseases in Jiangxi Province (2024SSY06101) and the Jiangxi Clinical Research Center for Gastroenterology (20223BCG74011). We appreciate Dr. Zhongming Ge for kindly providing the H. pylori 7.13 and PMSS1 strains. We also thank the TCGA, GEO, GEPIA, TIMER, Kaplan-Meier plotter and cBioPortal databases for providing data.

Funding

This research was funded by the National Natural Science Foundation of China (82270593), the China Postdoctoral Science Foundation (2023M731495), the Science and Technology Research Project of Jiangxi Provincial Department of Education (GJJ2400123) and the Science and Technology Plan of Jiangxi Provincial Health Commission (202510024).

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Author notes

  1. These authors contributed equally: Rulin Zhao, Jun Xie, Hao Chen, Xiaomin Gong.

Authors and Affiliations

  1. Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Rulin Zhao, Jun Xie, Hao Chen, Xiaomin Gong, Chao Peng, Jinliang Xie, Jianxiang Peng, Jiayu Qiu, Chengyun Wu, Dingwei Liu, Wenjie Ding, Sihai Chen, Xiaoling Gong, Huan Wang, Jianfang Rong, Jianping Liu & Yong Xie

  2. Department of Clinical Laboratory, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Rulin Zhao

  3. Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China

    Rulin Zhao

  4. Department of Drug Safety Evaluation Center, Jiangxi Medical Device Testing Center, Nanchang, Jiangxi, China

    Xidong Wu

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Contributions

JL and YX were responsible for designing, conceiving, and supervising the study, and the experiments were conducted by RZ, JX, HC and XG. CP, JX, JP, JQ, CW, XG, HW, JR, WD and XW collected the clinical samples and contributed to the animal experiments. The bioinformatics analysis was conducted by CP, DL and SC. RZ drafted the manuscript, while JL and YX edited the paper.

Corresponding authors

Correspondence to Jianping Liu or Yong Xie.

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The authors declare no competing interests.

Ethics approval and consents to participate

The study was approved by the Ethics Committee of The First Affiliated Hospital of Nanchang University (Approval No. 2020-1-64). All tissue samples were collected with informed consent. All studies involving animals were performed following the ARRIVE guidelines (https://arriveguidelines.org).

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Zhao, R., Xie, J., Chen, H. et al. VASN drives gastric tumorigenesis via activation of the COL4A1/PI3K/AKT axis during Helicobacter pylori infection. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03081-7

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