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SNX5 facilitates the progression of gastric cancer by increasing the membrane localization of LRP5

Oncogene volume 44, pages 1182–1196 (2025)Cite this article

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Abstract

Endocytosis is essential for cancer cell motility, which is predominantly mediated by the sorting nexin (SNX) family. Previous studies have demonstrated that SNX5 is elevated in several tumors, while its clinical significance and underlying mechanism in gastric cancer (GC) remain uninvestigated. In this study, we reported that SNX5 is highly expressed in GC and promotes the malignant biological behavior of GC cells. Its upregulation is closely related to poor prognosis in GC patients. Mechanistically, we observed an interaction between SNX5 and low-density lipoprotein receptor-related protein5 (LRP5) in GC cells. SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, which prevents LRP5 from being degraded in the lysosome. The increased membrane localization of LRP5 facilitates β-catenin stabilization, thus activating the Wnt signaling pathway, leading to tumorigenesis and progression.

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Fig. 1: Elevated SNX5 expression correlates with aggressive characteristics and unfavorable prognosis in GC patients.
Fig. 2: SNX5 regulates the proliferation, migration, and invasion of GC cells in vitro.
Fig. 3: SNX5 positively regulates β-catenin and LRP5 expression in GC cells.
Fig. 4: SNX5 inhibits the internalization and degradation of LRP5.
Fig. 5: SNX5 directly regulates the transport of LRP5.
Fig. 6: SNX5 promotes GC progression through the Wnt/β-catenin pathway.
Fig. 7: Silencing SNX5 inhibits the growth of GC cells in vivo.
Fig. 8: Schematic diagram of GC progression mediated by SNX5 through inhibition of LRP5 internalization and subsequent degradation.

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Data availability

The data generated in this study are available within the article and its supplementary information files.

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Acknowledgements

We sincerely thank the Shanghai Institute of Cell Biology and the Chinese Academy of Sciences for providing human gastric epithelial GES-1 and GC cell lines (AGS, SNU-719, SGC-7901, MGC-803, HGC-27, and MKN-45).

Funding

Our study was funded in part by Natural Science Foundation of China (82160464, 82360577, 82160459, and 82060566), Special fund for innovation of Postgraduates in Jiangxi Province (YC2022—B055), “Double Thousand” project for training high-level talents of scientific and technological innovation in Jiangxi Province (jxsq2023201038), Academic leader Project of Jiangxi Province (20225BCJ23004), Leading medical research project of Nanchang University (ZL101), Natural Science Foundation of Jiangxi Province (20224BAB216060) and Jiangxi Key Laboratory for Individualized Cancer Therapy (20202BCD42011).

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  1. These authors contributed equally: Yi Le, Ling Zhou.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1519 Dongyue Avenue, Nanchang, 330006, Jiangxi, China

    Yi Le, Ling Zhou, Yan He, Juanjuan Zhou, Jinbo Zhan, Hongjiao Zhang, Xiao Chen, Jianping Xiong, Ziling Fang & Xiaojun Xiang

  2. Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, 17 Yongwai Street, Nanchang, 330006, Jiangxi, China

    Yi Le, Ling Zhou, Yan He, Juanjuan Zhou, Jinbo Zhan, Hongjiao Zhang, Xiao Chen, Jianping Xiong, Ziling Fang & Xiaojun Xiang

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Contributions

Yi Le, Ling Zhou, and Xiaojun Xiang initiated and designed the project. Yi Le, Ling Zhou, and Ziling Fang wrote the manuscript. Yi Le, Yan He, Juanjuan Zhou, and Hongjiao Zhang conducted experiments and collected data; Gene set enrichment analysis was performed by Jinbo Zhan. Xiao Chen analyzed the data. Xiaojun Xiang, Ziling Fang, and Jianping Xiong are responsible for overseeing the design structure of the manuscript, reviewing and helping to revise the manuscript. All authors have read and approved the manuscript.

Corresponding authors

Correspondence to Jianping Xiong, Ziling Fang or Xiaojun Xiang.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study has been approved by the Medical Research Ethics Committee of the First Affiliated Hospital of Nanchang University (approval number: (2024) CDYFYYLK (12-074)). Informed consent was obtained from all patients prior to participation. All animal experiments in this study were approved by the Animal Welfare and Ethics Committee of the First Affiliated Hospital of Nanchang University, with the ethical approval number CDYFY-IACUC-202208QR008. All methods were carried out in accordance with relevant guidelines and regulations.

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Le, Y., Zhou, L., He, Y. et al. SNX5 facilitates the progression of gastric cancer by increasing the membrane localization of LRP5. Oncogene 44, 1182–1196 (2025). https://doi.org/10.1038/s41388-025-03298-z

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