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Dongshao Chen,1,* Xiaoting Lin,1,* Cheng Zhang,1 Guo An,2 Zhongwu Li,3 Bin Dong,3 Lin Shen,1 Jing Gao,1 Xiaotian Zhang1 1Department of Gastrointestinal Oncology; 2Department of Laboratory Animal; 3Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China *These authors contributed equally to this work Background: Characterized by elevated AFP levels in serum, AFP-producing gastric cancer (APGC) is a very special type of gastric cancer (GC) that is difficult to treat and has poor prognosis. However, little is known about the role of AFP in GC, which was investigated in this study with in vitro and in vivo experiments. Methods: APGC cells were established with lentivirus infection and validated by PCR assay and ELISA in HCG27 and AGS cells. Cell growth, migration, and invasion were determined by CCK8, transwell assays, and animal experiments. RNA sequencing, Western blot, dual-luciferase-reporter assays, and RNA interference were employed to understand mechanisms underlying AFP activity, followed by therapeutic investigations for APGC. Results: APGC cells featured significantly increased AFP levels in cellular supernatants. AFP potentiated growth and aggression in GC cell lines and their derived xenografts. Wnt-signaling activation was responsible for AFP function, indicated by decreased Axin 1 and pGSK3β, followed by cascade activation of β-catenin, downstream transcription factors TCF1/TCF7, and the target gene – c-Myc. Wnt-signaling blockade by Axin 1 rescue or pathway inhibitor XAV939 reversed AFP function, suggesting the potential therapeutic value of APGC. Conclusion: AFP played a critical role in APGC through activating Wnt signaling, and targeting Wnt pathways might be a promising strategy against APGC. Keywords: alpha-fetoprotein, AFP, AFP-producing gastric cancer, APGC, Axin 1, Wnt signaling, Wnt-signaling inhibitor