Biochimica et biophysica acta. Molecular basis of disease · 2026
B3GNT2 promotes gastric cancer metastasis by facilitating membrane trafficking of RYK via N-glycosylation.
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Fu Yongan, Wang Yangqiang, Cai Zongda, Huang Shurong, Chen Jinping, Ye Jianxin
Аннотация
BACKGROUND: Gastric cancer (GC) is characterized by a high metastatic propensity, which constitutes the primary cause of poor patient prognosis. Receptor-like tyrosine kinase (RYK) is associated with GC metastasis, but its regulatory mechanism remains unclear.
METHODS: Primary and metastatic GC tissues, together with their matched adjacent non-tumor samples, were collected. GC cell models were established to systematically evaluate the driver role of RYK in GC metastasis. We further integrated clinical specimens, GC cell models, and a mouse model of GC liver metastasis, and combined immunohistochemistry, real-time quantitative PCR, Western blot, flow cytometry, immunofluorescence, wound-healing assays, 3D sphere invasion assays, and co-immunoprecipitation to elucidate the biological functions and molecular mechanisms of RYK in GC metastasis.
RESULTS: RYK expression was higher in both primary and metastatic tumor tissues than in adjacent normal tissues. Overexpression of RYK markedly enhanced the invasion and migration capacities of GC cells and induced epithelial-to-mesenchymal transition; blocking its membrane localization promptly attenuated this pro-metastatic effect. Mechanistically, β-1,3-N-acetylglucosaminyltransferase 2 (B3GNT2) bound to RYK and catalyzed its N-glycosylation, thereby promoting RYK trafficking to the plasma membrane. In GC cell models and a liver-metastasis mouse model, GC cells overexpressing B3GNT2 displayed significantly increased metastatic ability, whereas treatment with an N-glycosylation inhibitor effectively suppressed this phenomenon.
CONCLUSION: B3GNT2 promotes the trafficking of RYK to the plasma membrane of GC cells by mediating its N-glycosylation, thereby driving GC metastasis.
METHODS: Primary and metastatic GC tissues, together with their matched adjacent non-tumor samples, were collected. GC cell models were established to systematically evaluate the driver role of RYK in GC metastasis. We further integrated clinical specimens, GC cell models, and a mouse model of GC liver metastasis, and combined immunohistochemistry, real-time quantitative PCR, Western blot, flow cytometry, immunofluorescence, wound-healing assays, 3D sphere invasion assays, and co-immunoprecipitation to elucidate the biological functions and molecular mechanisms of RYK in GC metastasis.
RESULTS: RYK expression was higher in both primary and metastatic tumor tissues than in adjacent normal tissues. Overexpression of RYK markedly enhanced the invasion and migration capacities of GC cells and induced epithelial-to-mesenchymal transition; blocking its membrane localization promptly attenuated this pro-metastatic effect. Mechanistically, β-1,3-N-acetylglucosaminyltransferase 2 (B3GNT2) bound to RYK and catalyzed its N-glycosylation, thereby promoting RYK trafficking to the plasma membrane. In GC cell models and a liver-metastasis mouse model, GC cells overexpressing B3GNT2 displayed significantly increased metastatic ability, whereas treatment with an N-glycosylation inhibitor effectively suppressed this phenomenon.
CONCLUSION: B3GNT2 promotes the trafficking of RYK to the plasma membrane of GC cells by mediating its N-glycosylation, thereby driving GC metastasis.