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Gastric cancer (GC) is one of the most common and lethal malignancies worldwide,and its poor prognosis is mainly due to the rapid tumor progression including tumor invasion,distant metastasis,etc.Understanding the molecular mechanisms regulating GC progression lays the basis for the development of targeted therapeutic agents.Increasing evidence suggests that guanine nucleotide-binding protein subunit beta-4 (GNB4),a key subunit of heterotrimeric G protein,plays a crucial role in the initiation and progression of multiple malignancies.However,whether and how GNB4 promotes GC progression are still unknown.In this study,we found that GNB4 was highly expressed in GC tissues compared to that in non-tumor tissues and was significantly associated with tumor invasion depth,pathological stage and poor survival rate of GC patients.Both gain-of-function and loss-of-function studies revealed that GNB4 significantly enhanced GC cell growth and motility both in vitro and in vivo.Further studies revealed that GNB4 overexpression induced G1-S transition and promoted the process of epithelial-mesenchymal transformation.These tumor promoting effects were mediated by GNB4 which activates the Erk1/2 pathwaythrough upregulating Erk1/2 phosphorylation,as U0126,an Erk1/2 phosphorylation inhibitor,could significantly inhibit GNB4-mediated cell proliferation,migration and invasion.In summary,GNB4 contributes to the proliferation and metastasis of GC cells by activating the Erk1/2 signaling pathway,and it may serve as a potential therapeutic target of GC.