Abstract

Syntaphilin (SNPH), initially considered a neuron-specific protein, has recently been found to be widely expressed across various cancers. Mechanistically, SNPH inhibits mitochondrial transport to the cortical cytoskeleton, thereby suppressing cancer cell migration and metastasis. Although SNPH is known to participate in the metastatic progression of multiple malignancies, its precise underlying mechanism remains obscure. In this study, we investigated the role of SNPH in the epithelial–mesenchymal transition (EMT) and invasiveness of gastric cancer cells. Knockdown of SNPH in SNU-638 gastric cancer cells significantly enhanced their migratory and invasive capacities by approximately 1.4-fold and 2.5-fold, respectively. This knockdown concurrently increased focal adhesion kinase (FAK) phosphorylation, upregulated the EMT marker vimentin, and increased the expression of key EMT-related transcription factors, including Snail, Slug, and Twist. Furthermore, SNPH depletion induced the phosphorylation of nuclear factor kappa B (NF-κB), a transcription factor regulating matrix metalloproteinase-9 (MMP-9), which subsequently upregulated MMP-9 mRNA expression. This cascade promotes extracellular matrix degradation, thereby increasing metastatic potential. Notably, these phenotypic and molecular changes were completely reversed upon SNPH overexpression in SNU-638 cells. Taken together, our results demonstrate that SNPH deficiency enhances the migration and metastatic potential of gastric cancer cells by driving EMT and invasion via the FAK/NF-κB/MMP-9 signaling pathway. Consequently, we propose that SNPH represents a novel biomarker and a promising therapeutic target for mitigating gastric cancer metastasis.

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