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The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells

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Abstract

Purpose

Gastric cancer (GC) is a malignant tumour with high mortality, and liver metastasis is one of the main causes of poor prognosis. SLIT- and NTRK-like family member 4 (SLITRK4) plays an important role in the nervous system, such as synapse formation. Our study aimed to explore the functional role of SLITRK4 in GC and liver metastasis.

Methods

The mRNA level of SLITRK4 was evaluated using publicly available transcriptome GEO datasets and Renji cohort. The protein level of SLITRK4 in the tissue microarray of GC was observed using immunohistochemistry. Cell Counting Kit-8, colony formation, transwell migration assays in vitro and mouse model of liver metastasis in vivo was performed to investigate the functional roles of SLITRK4 in GC. Bioinformatics predictions and Co-IP experiments were applied to screen and identify SLITRK4-binding proteins. Western blot was performed to detect Tyrosine Kinase receptor B (TrkB)-related signaling molecules.

Results

By comparing primary and liver metastases from GC, SLITRK4 was found to be upregulated in tissues of GC with liver metastasis and to be closely related to poor clinical prognosis. SLITRK4 knockdown significantly abrogated the growth, invasion, and metastasis of GC in vitro and in vivo. Further study revealed that SLITRK4 could interact with Canopy FGF Signalling Regulator 3 (CNPY3), thus enhancing TrkB- related signaling by promoting the endocytosis and recycling of the TrkB receptor.

Conclusion

In conclusion, the CNPY3-SLITRK4 axis contributes to liver metastasis of GC according to the TrkB-related signaling pathway. which may be a therapeutic target for the treatment of GC with liver metastasis.

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Data availability

The Gene Expression Omnibus (GEO) datasets involved in the study include GSE65801 and GSE30601. GSE65801 contains gene expression microarray analyses of 32 GC tissues and 32 paired noncancerous tissues, while GSE30601 contains genome-wide DNA methylation profiles of 203 GC tissues and 94 paired noncancerous tissues. Transcriptomic data from the PRJNA555812 project stored in the Sequence Read Archive (SRA) were used to analyse transcriptional changes in liver metastasis of gastric cancer. The Renji Cohort used in our study comprised 69 GC liver metastatic tissues collected from 2005 to 2011; data collected also included RNA sequencing analyses, tissue microarrays, and corresponding retrospective analyses.

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Funding

This study was supported by the National Natural Science Foundation of China (No. 82073023, 81871923, to J. Li; No.82103357 to L.P. Hu; No. 82002485, to Q. Li; No. 31801212, to L.L. Yao; No. 82103348, to Y.Y. Wang), the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20191809, to J. Li), the Natural Science Foundation of Shanghai (No.21ZR1461300 to L.P. Hu; No. 22ZR1460000 to X.L. Zhang), Shanghai Sailing Program (No.21YF1445200 to L.P. Hu), Innovative research team of high-level local universities in Shanghai, the Shanghai Municipal Health Commission (No. 202040092 to X.L. Zhang).

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Author notes

  1. Yao-Qi Zhou, Tian-Shang Bao, Jia-Xuan Xie and Lin-Li Yao contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, People’s Republic of China

    Yao-Qi Zhou, Jia-Xuan Xie, Lin-Li Yao, Qing Li, Pei-Qi Huang, Su-Yuan Chen, Xiao-Qi Wang, Xue-Li Zhang, Shu-Heng Jiang, Zhi-Gang Zhang, Li-Peng Hu & Jun Li

  2. Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Tian-Shang Bao, Si-Te Yu, Yang-Yang Wang & Jia Xu

  3. Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Wan-Zhen Zhou

  4. Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Hachioji, Japan

    Shuang-Qin Yi

  5. Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China

    Ming-Ze Ma

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  1. Yao-Qi Zhou
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  19. Jun Li
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Contributions

L-PH, JX, and JL conceived the project and designed experiment. T-SB, S-TY, QL, Y-YW collected clinical information and performed bioinformatics analyses. Y-QZ, J-XX, P-QH, S-YC, W-ZZ, X-QW conducted the experiments. L-LY, X-LZ, S-HJ and S-QY analyzed data. Y-QZ and J-XX wrote the manuscript and made the figures. Z-GZ, M-ZM, L-PH, JX, and JL supervised this study and edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ming-Ze Ma, Li-Peng Hu, Jia Xu or Jun Li.

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Zhou, YQ., Bao, TS., Xie, JX. et al. The SLITRK4-CNPY3 axis promotes liver metastasis of gastric cancer by enhancing the endocytosis and recycling of TrkB in tumour cells. Cell Oncol. 46, 1049–1067 (2023). https://doi.org/10.1007/s13402-023-00795-9

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