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

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 metastatasis in vivo were 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 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-SLITRK 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.

Exploring the association between inflammatory biomarkers and gastric cancer development: A two-sample mendelian randomization analysis.

“…The signaling pathways involving tissue factor and IL-6R can mutually influence one another, thus intensifying the activation of inflammatory cells and cytokine release. [34,35] FABP4, integral to both fatty acid metabolism and the inflammatory response, interacts with these markers, contributing to the broader inflammatory milieu. [36,37] The Mendelian randomization approach is an increasingly utilized methodological design in medical research, particularly pertinent in discerning the complex interplay between inflammation and gastric carcinogenesis.…”

“…The signaling pathways involving tissue factor and IL-6R can mutually influence one another, thus intensifying the activation of inflammatory cells and cytokine release. [34,35] FABP4, integral to both fatty acid metabolism and the inflammatory response, interacts with these markers, contributing to the broader inflammatory milieu. [36,37]…”