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Graphical abstract Abstract PRSS23 is a newly discovered serine protease that has been associated with tumor progression in various types of cancers. Our previous study showed PRSS23 is down-regulated obviously in Hedgehog pathway blocked gastric cancer cells. However, the correlation between PRSS23 and tumor progression of gastric cancer remains unclear. Here, the role and mechanism of PRSS23 in tumor progression of gastric cancer were determined. PRSS23 protein levels were significantly increased in gastric cancer tissues compared with the paired adjacent normal gastric mucosa tissues. The high expression of PRSS23 correlated strongly with both poor differentiated histology and cancer region of sinus ventriculi. Gastric cancer patients with low PRSS23 expression displayed a better prognosis. In gastric cancer cells, PRSS23 knockdown inhibited cell proliferation and induced apoptosis. In xenograft tumor model, PRSS23 knockdown led to dramatic decreases of the average tumor volume and the average tumor weight. In addition, PRSS23 knockdown suppressed gastric cancer growth through inhibiting EIF2 signaling using gene expression microarray analysis. Taken together, our results suggest PRSS23 is highly associated with human gastric tumorigenesis and progression. PRSS23 knockdown could suppress tumor growth of gastric cancer in vitro and in vivo through inhibiting EIF2 signaling, and EIF4E maybe a potential target of PRSS23. PRSS23 could serve as a potential target for gastric cancer therapy, and also a biomarker for the prediction of prognosis of gastric cancer. [ABSTRACT FROM AUTHOR]