PCK1 promotes gastric cancer progression by activating the SRC1-JAK1-STAT3 signaling axis

BACKGROUND: Phosphoenolpyruvate carboxykinase 1 (PCK1) has been shown to have signalling functions beyond gluconeogenesis. However, its role in gastric cancer is unclear. OBJECTIVE: To determine the clinical significance, biological function and molecular mechanism of PCK1 in gastric cancer. METHODS: PCK1 expression and prognostic value were evaluated using public databases and validated in gastric cancer tissues and cell lines. The effects of PCK1 knockdown in AGS and HGC-27 cells were assessed using CCK-8, colony formation, Transwell and wound-healing assays. The underlying mechanism was investigated using transcriptomic analysis, protein interaction analysis, qRT-PCR, Western blotting, co-immunoprecipitation, SRC1 rescue experiments and nude-mouse xenograft models. The associations between PCK1 and the tumour immune microenvironment were also analysed. RESULTS: PCK1 was found to be upregulated in gastric cancer and to be associated with a poor prognosis. Knockdown of PCK1 suppressed cell viability, clonogenicity, migration, invasion and xenograft growth, reduced Ki-67 expression and increased cleaved caspase-3 expression. PCK1 formed a protein complex with SRC1; however, its knockdown decreased SRC1 expression, as well as JAK1 and STAT3 phosphorylation and PD-L1 expression. SRC1 overexpression partially reversed these molecular and phenotypic effects. PCK1 expression was associated with immune cell infiltration but showed no clear relationship with the overall TIDE score or predicted immunotherapy response. CONCLUSION: PCK1 promotes gastric cancer progression partly through the SRC1/JAK1/STAT3 axis and regulation of PD-L1, suggesting its potential as a therapeutic target. However, its immunomodulatory and predictive value requires further validation.