Neuropilin 1 Drives Gastric Cancer Growth and Metastasis by Regulating Copper Homeostasis

Background: Gastric cancer (GC) is considered a significant health problem worldwide. The initial diagnosis of GC often occurs at an advanced disease stage and the prognosis is generally poor. The objective of this study is to investigate the role of neuropilin 1 (NRP1) in driving growth and metastasis of gastric cancer through the regulation of copper homeostasis. Our aim is to develop potential novel therapeutic strategies for GC.Methods: Gene expression profiling and clinical data from gastric cancer patients were obtained from The Cancer Genome Atlas (TCGA). Differential analysis was performed using the limma package in R, and a prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression. The diagnostic model was established using logistic regression. Cell culture experiments were conducted to validate the findings, including reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), western blotting, cell counting kit (CCK)-8 assay, colony-forming assay, cell scratch test, transwell migration assay, immunofluorescence staining, and apoptosis analysis.Results: NRP1 was found to be overexpressed in gastric cancer cells (p < 0.01). It was identified as a potential regulator of copper homeostasis, as its overexpression led to increased expression levels of ATPase copper transporting alpha (ATP7A; p < 0.01), a copper transporter. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was involved in mediating the effects of NRP1 on ATP7A expression. Functional assays demonstrated that NRP1 promoted cell proliferation (p < 0.05) and migration (p < 0.01), while inhibiting apoptosis (p < 0.05). Furthermore, treatment with a copper chelator sensitized NRP1-overexpressing cells and reduced their proliferation (p < 0.01).Conclusions: This study reveals that NRP1 plays a crucial role in driving the growth and metastasis of gastric cancer through the regulation of copper homeostasis. Targeting NRP1 and copper homeostasis may provide potential therapeutic strategies for the treatment of gastric cancer.