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LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis

Oncogene volume 44, pages 652–664 (2025)Cite this article

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Abstract

Gastric cancer ranks among the most prevalent malignancies globally, characterized by limited treatment efficacy and high recurrence rates. Effective management of this disease requires a comprehensive understanding of its underlying pathogenic mechanisms. Galectins have emerged as promising targets in gastric cancer therapy, with Galectin-9 (LGALS9) receiving considerable attention in recent years. However, Galectin-9B (LGALS9B) remains relatively under-explored in gastric cancer research. Our study investigates the role of LGALS9B in gastric cancer progression, demonstrating that its over-expression enhances cellular proliferation, migration, and invasion, while its knockdown inhibits these processes both in vitro and in vivo. We further elucidate that LGALS9B competes with the E3 ligase HERC5 for binding to eukaryotic translation elongation factor 1 delta (EEF1D), thereby preventing its protein degradation. This interaction results in the enrichment of EEF1D, which activates the PI3K/AKT signaling pathway and ultimately promotes gastric cancer progression. These findings highlight the regulatory role of LGALS9B in the pathogenesis of gastric cancer, offering valuable insights into potential novel therapeutic strategies for managing this challenging disease.

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Fig. 1: LGALS9B promoted the proliferation, migration and invasion of AGS and N87 cells.
Fig. 2: Knockdown of LGASL9B inhibited the proliferation, migration and invasion of AGS and N87 cells.
Fig. 3: Overexpression of LGASL9B promoted the AGS proliferation in vivo.
Fig. 4: LGASL9B regulated PI3K/AKT pathway by interacting with EEF1D.
Fig. 5: LGASL9B and EEF1D regulated the cell cycle of AGS cells.
Fig. 6: EEF1D promoted the proliferation, migration, and invasion of AGS and N87 cells.
Fig. 7: LGASL9B regulated EEF1D expression through HERC5.
Fig. 8: LGALS9B promoted the proliferation, migration and invasion of gastric cancer cells by regulating EEF1D.

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Data availability

All data in our study are available upon request.

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Funding

This work was supported by the National Natural Science Foundation of China (32370836 to Y Li), Medical Scientific Research Foundation of Guangdong Province of China (B2022168 to JB Zheng), and Guangdong Basic and Applied Basic Research Foundation (2024A1515012829 to Y Li).

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Author notes

  1. These authors contributed equally: Huolun Feng, Wei Yao, Yucheng Zhang, Yongfeng Liu.

Authors and Affiliations

  1. School of Medicine, South China University of Technology, Guangzhou, Guangdong, China

    Huolun Feng, Yong Li & Jiabin Zheng

  2. Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Huolun Feng, Yucheng Zhang, Yongfeng Liu, Ji Zhou, Jiehui Li, Zhuosheng Jiang, Fa Ling, Jianlong Zhou, Deqing Wu, Yong Li & Jiabin Zheng

  3. Ganzhou Hospital of Guangdong Provincial People’s Hospital, Ganzhou Municipal Hospital, Ganzhou, China

    Huolun Feng, Bin Liu, Yong Li & Jiabin Zheng

  4. State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China

    Wei Yao & Juan Yang

  5. Gannan Medical University, Ganzhou, China

    Bin Liu

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Contributions

Huolun Feng, Wei Yao, Yucheng Zhang and Yongfeng Liu designed this study; Yucheng Zhang, Huolun Feng, Wei Yao and Ji Zhou performed the experiments; Yongfeng Liu, Bin Liu, Jiehui Li and Zhuosheng Jiang conducted RNA-Seq analyses; Fa Ling and Jianlong Zhou executed the IP-MS analysis; Huolun Feng, Deqing Wu, Yucheng Zhang and Yongfeng Liu analyzed and interpreted the data; Huolun Feng, Yucheng Zhang drafted the manuscript, Huolun Feng and Wei Yao edited the manuscript. Wei Yao, Juan Yang, Yong Li, and Jiabin Zheng provided oversight and supervision throughout this study.

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Correspondence to Yong Li, Juan Yang or Jiabin Zheng.

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All methods were performed in accordance with the relevant guidelines and regulations. All animal procedures were reviewed and approved by the Animal Care and Use Committee of the Topbiotech Biotechnology Co., Ltd. SYXK 2023-0315. This work does not involve informed consent and human research.

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Feng, H., Yao, W., Zhang, Y. et al. LGALS9B stabilizes EEF1D protein and activates the PI3K/AKT signaling pathway to promote gastric cancer occurrence and metastasis. Oncogene 44, 652–664 (2025). https://doi.org/10.1038/s41388-024-03247-2

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