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OBJECTIVE Gastric cancer is one of the most common gastrointestinal malignancy, which is often diagnosed at an advanced stage. MicroRNA-105 (miR-105) was downregulated and acts as a tumor suppressor in various cancers. The purpose of this study was to explore the molecular mechanisms of miR-105 and sex-determining region Y-box 9 (SOX9) in gastric cancer. PATIENTS AND METHODS Western blot was performed to display the protein level of E-Cadherin, N-Cadherin, Vimentin and SOX9. Transwell assay was utilized to measure the capacity of migration and invasion. We employed the Luciferase reporter assay to determine miR-105 targeting to SOX9 in gastric cancer. RESULTS MiR-105 was downregulated in gastric cancer tissues and cells; it suppressed gastric cancer cell migration, invasion and epithelial-mesenchymal transition (EMT) in gastric cancer. SOX9 was upregulated in gastric cancer cells and had a negative correlation with miR-105. Moreover, the knockdown of SOX9 could inhibit gastric cancer cell migration, invasion and EMT. Furthermore, SOX9 was a target gene of miR-105 and mediated by miR-105. SOX9 could reverse the partial function of miR-105 on cell migration and invasion. In addition, miR-105 downregulation or SOX9 upregulation predicted a poor prognosis. CONCLUSIONS We showed that miR-105 was downregulated and inhibited cell migration, invasion and EMT in gastric cancer by binding to SOX9. In addition, we demonstrated that miR-105 downregulation or SOX9 upregulation predicted a poor prognosis. The newly discoverable miR-105/SOX9 axis provides novel insight into gastric cancer treatment.