SLC38A7 promotes gastric cancer progression through activating Wnt/β-catenin signaling via interaction with MYH9

Background: Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. Solute carrier family 38 member 7 (SLC38A7), a lysosome-localized glutamine transporter, has been implicated in poor cancer prognosis and chemoresistance, but its biological role in GC is not well understood. This study aimed to investigate the biological function of SLC38A7 in GC progression and to elucidate the underlying signaling mechanism. Methods: The expression pattern and clinical relevance of SLC38A7 were analyzed using public datasets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, and validated in 60 paired GC tissues collected at the Chinese People’s Liberation Army (PLA) General Hospital. Gain- and loss-of-function experiments were conducted in MKN-28 and MGC-803 to evaluate the effects of SLC38A7 on cell proliferation, migration, and invasion under glutamine-replete and glutamine-deprived conditions. Protein–protein interactions were assessed by co-immunoprecipitation and mass spectrometry. Site-directed mutagenesis was performed to identify key residues mediating SLC38A7 function. Downstream signaling was analyzed by western blotting and ubiquitination assays. A xenograft mouse model was established to determine the role of SLC38A7 in tumor growth in vivo . Results: SLC38A7 expression was significantly upregulated in GC tissues and cell lines and was associated with poor patient prognosis. Functional assays demonstrated that SLC38A7 promoted GC cell proliferation, migration, and invasion, particularly under glutamine-deprived conditions. Mechanistically, SLC38A7 interacted with myosin heavy chain 9 (MYH9), facilitating glycogen synthase kinase-3β (GSK-3β) ubiquitination and degradation, which led to activation of the wingless/int-1 (Wnt)/β-catenin signaling pathway. Mutation of key SLC38A7 residues (E12 and Q3) disrupted its interaction with MYH9 and attenuated downstream signaling. Pharmacological inhibition of GSK-3β partially rescued the effects of SLC38A7 silencing in vitro . In vivo , SLC38A7 knockdown significantly suppressed tumor growth. Conclusion: SLC38A7 promotes gastric cancer progression by activating the Wnt/β-catenin signaling pathway through MYH9-dependent regulation of GSK-3β ubiquitination.