miR-21 is an abundantly expressed miRNA in mammalian cells, and evolutionarily conserved across a wide range of vertebrate species. The previous study found that miR-21 is significantly upregulated in gastric cancer. However, the detail mechanisms remain to be largely unknown. In current study, quantitative real-time PCR was applied to examine the expression of miR-21 in gastric cancer tissue and cell lines. The roles of miR-21 in cell proliferation and cell cycle were analyzed by cck8 cell viability assays, flow cytometry cell cycle assays and clone formation assays. As to detail mechanisms, we investigate the relationship between miR-21 and 15-PGDH in gastric cell lines, AGS and BGC-823 treated with In-miR-21, and found that miR-21 is negatively correlated with 15-PGDH. The reduced 15-PGDH may result in PGE2 accumulation which sustains carcinogenesis and tumor progression. We further found that miR-21 exert its oncogenic role through PGE/PI3K/Akt/Wnt/β-catenin axis in gastric cell proliferation. In conclusion, our findings enlarged our knowledge in the roles of miR-21 in the progression of gastric cancer.