Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025061
Glutamine metabolism is a hallmark of cancer metabolism. This study aims to perform a comprehensive and systematic single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions. We use single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC) lesions and investigate glutamine metabolism features at the single-cell level. Experiments are implemented to validate the expression and biological role of ERO1LB in gastric cancer (GC). A single-cell atlas based on 22511 cells from premalignant and early-malignant gastric lesions is established. Among these cells, epithelial cells constitute the dominant cell population in both CAG and EGC lesions. The activity of glutamine metabolism is higher in epithelial cells from EGC lesions than in those from CAG lesions. Among the epithelial cell subpopulations, glutamine metabolism is more active in the epithelial cell subpopulation cluster_4 in EGCs than in CAG lesions. As a key marker gene of this subpopulation, ERO1LB is experimentally proven to be overexpressed in human GC tissue lesions. In both in vitro and in vivo experiments, overexpression of ERO1LB in GC cells increases glutamine metabolism, facilitates cell growth and migration and prevents cell apoptosis, and vice versa. This study provides insight into the cellular heterogeneity of glutamine metabolism within the gastric mucosa in premalignant and malignant gastric lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, which may help to identify markers for GC prevention and contribute to our understanding of GC pathogenesis.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025061
Glutamine metabolism is a hallmark of cancer metabolism. This study performed a comprehensive single-cell profile of glutamine metabolism in premalignant and malignant gastric lesions using single-cell transcriptomics data from chronic atrophic gastritis (CAG) and early gastric cancer (EGC). A single-cell atlas based on 22,511 cells was established. Epithelial cells constituted the dominant population in both CAG and EGC lesions. Glutamine metabolism activity was higher in epithelial cells from EGC than in those from CAG. Among epithelial subpopulations, cluster_4 exhibited elevated glutamine metabolism in EGC. ERO1LB, a key marker gene of this subpopulation, was experimentally validated to be overexpressed in human GC tissue lesions. In vitro and in vivo experiments demonstrated that ERO1LB overexpression in GC cells increased glutamine metabolism, facilitated cell growth and migration, and prevented apoptosis, while targeted suppression reversed these effects. The study provides insight into the cellular heterogeneity of glutamine metabolism within the gastric mucosa in premalignant and malignant lesions and identifies ERO1LB as a key orchestrator of glutamine metabolism, potentially aiding in the identification of markers for GC prevention and contributing to the understanding of GC pathogenesis. Limitations include the preliminary nature of the evidence for ERO1LB's role in CAG-induced carcinogenesis, necessitating further mechanistic studies.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025202
Gastric cancer (GC) remains the fifth most common malignancy and third leading cause of cancer-related mortality worldwide, with over 60% of cases occurring in East Asia. Despite advances in endoscopic screening and perioperative FLOT regimens, the 5-year survival rate for advanced or metastatic GC is still below 20%. This study investigates the expression and mechanistic role of V-set and immunoglobulin domain containing 2 (VSIG2) in GC progression. Western blot, qRT-PCR, and immunohistochemical staining revealed that VSIG2 is abnormally downregulated in GC tissues and cells, and its low expression correlates with tumor size, lymph node metastasis, TNM stage, and vascular invasion. Kaplan-Meier analysis confirmed that reduced VSIG2 expression is associated with poor patient prognosis. Functional assays, including CCK-8, EdU, Transwell, and wound healing in vitro, as well as nude mouse subcutaneous tumor and liver metastasis models in vivo, demonstrated that VSIG2 inhibits GC growth, proliferation, and metastasis. Mechanistically, co-immunoprecipitation and immunofluorescence showed that VSIG2 directly interacts with ANXA2 and co-localizes at the cell membrane. VSIG2 competes with FBXW10 for ANXA2 binding, relying on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce its membrane localization and subsequent inactivation of NF-κB signaling. These findings establish VSIG2 as a membrane-localized tumor suppressor that restrains GC progression by blocking the ANXA2–FBXW10–NF-κB axis, offering a potential therapeutic target for high-risk gastric cancer patients.