Background and Aims Transmembrane proteins (TMEMs) are a class of proteins that span the entire lipid bilayer. TMEM117 is an important member of the TMEM family, and previous research has shown that TMEM117 plays a significant role in regulating blood sugar, preventing myocardial hypertrophy, and participating in endoplasmic reticulum stress. However, the role of TMEM117 in gastric cancer (GC) remains unclear. Therefore, this study was conducted to explore the expression and biological functions as well as the action mechanisms of TMEM117 in GC.Methods Bioinformatics analysis was used to assess the expressions of TMEM117 in various cancer types. qRT-PCR and Western blot were employed to measure the expression levels of TMEM117 mRNA and protein in human normal gastric epithelial cells and different GC cell lines. qRT-PCR was also used to detect TMEM117 mRNA expression in GC tissue and corresponding adjacent tissue. TMEM117 was either knocked down or overexpressed in different GC cell lines, and its effects on GC cell function were assessed using CCK-8, EdU, and Transwell assays. Western blot analysis was conducted to examine the levels of relevant pathway proteins, and the impact of TMEM117 on GC cells was analyzed by adding specific inhibitor. Finally, the effects of TMEM117 knockdown on the growth of GC cells in nude mice were observed.Results Database analysis showed that TMEM117 was upregulated in various cancer tissues, and its expression in GC tissue was significantly higher than that in normal tissue (P<0.05). High expression of TMEM117 in GC was associated with poor prognosis (P<0.05). qRT-PCR and Western blot results revealed that TMEM117 mRNA and protein expressions in GC cells were significantly higher than those in normal gastric epithelial cells, and TMEM117 mRNA expression in GC tissue was significantly higher than that in adjacent tissue (all P<0.05). Functional experiments demonstrated that knocking down TMEM117 in GC cells significantly reduced proliferation, invasion, and migration, while overexpressing TMEM117 had the opposite effects (all P<0.05). Knocking down TMEM117 in GC cells resulted in a significant downregulation of TGF-β expression, while overexpressing TMEM117 in GC cells led to a significant upregulation of TGF-β expression; treatment with the TGF-β inhibitor LY2157299 partially reversed the promoting effect of TMEM117 overexpression on the malignant phenotype of GC cells (all P<0.05). In vivo tumor formation experiment in nude mice showed that knocking down TMEM117 significantly inhibited the growth of GC cells in the mice.Conclusion TMEM117 is highly expressed in GC and is closely associated with poor prognosis of patients. Its mechanism of promoting GC progression may be related to the activation of the TGF-β signaling pathway, which promotes the proliferation, invasion, and migration of GC cells. TMEM117 has the potential to be an effective target for GC treatment.