Cuproplasia-associated LOXL2 cooperates with Helicobacter pylori infection to promote gastric cancer progression via the FAK/Src signaling axis.

BACKGROUND: Gastric cancer (GC) remains a major cause of cancer-related mortality worldwide, and Helicobacter pylori (H. pylori) infection is a well-established carcinogenic driver. Cuproplasia, a recently proposed copper-dependent biological state characterized by hyperplasia, metaplasia, and neoplasia, has emerged as a potential mechanistic link between metabolic reprogramming and tumor progression. However, the contribution of cuproplasia-related genes to H. pylori-associated gastric carcinogenesis remains poorly defined. This study aimed to identify cuproplasia-associated genes linked to H. pylori-positive GC and to clarify the functional role and underlying mechanism of LOXL2 in H. pylori-associated gastric cancer progression. METHODS: Transcriptomic and clinical data were analyzed to construct a risk model for H. pylori-positive GC based on cuproplasia-related genes. Model performance was evaluated using receiver operating characteristic (ROC), nomogram, decision curve, and survival analyses. LOXL2 was subsequently selected for validation in clinical specimens by immunohistochemistry (IHC), western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional assays, including colony formation, wound healing, Transwell invasion, and mechanistic western blotting, were used to determine the biological effects of LOXL2 and H. pylori stimulation in GC cells. RESULTS: A five-gene cuproplasia-related signature showed strong predictive performance for H. pylori-positive GC. Among the candidate genes, LOXL2 emerged as the most prominent biomarker. LOXL2 was significantly overexpressed in H. pylori-infected GC tissues and was associated with tumor size, differentiation status, ​tumor-node-metastasis (TNM) stage, lymph node metastasis, distant metastasis, and H. pylori positivity. In vitro, LOXL2 overexpression enhanced GC cell proliferation, migration, and invasion, whereas LOXL2 knockdown exerted the opposite effects. H. pylori stimulation further amplified the tumor-promoting effects of LOXL2. Mechanistically, LOXL2 and H. pylori cooperatively increased FAK and Src phosphorylation, upregulated Snail, and suppressed E-cadherin expression, thereby facilitating epithelial-mesenchymal transition (EMT). CONCLUSIONS: Rather than serving merely as a prognostic biomarker, LOXL2 functions as a cuproplasia-associated effector that cooperates with H. pylori infection to promote GC progression through activation of the FAK/Src signaling pathway, thereby providing new insights into the molecular mechanisms underlying H. pylori-associated gastric carcinogenesis.