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MicroRNAs (miRNAs) have emerged as important gene regulators and are recognized as oncogenes or tumor suppressor genes in carcinogenesis. Gastric cancer is one of the most common malignant diseases worldwide. Our previous studies have revealed that miR-146a is upregulated in gastric epithelial cells infected with Helicobacter pylori (H. pylori) and in mucosal tissues from H. pylori-positive patients. However, the role of miR-146a in gastric cancer is largely unknown. In the current study, we showed that miR-146a was upregulated in 20 gastric cancer tissues compared with matched non-tumor adjacent tissues by quantitative RT-PCR. Furthermore, ectopic expression of miR-146a could improve cell proliferation in vitro by using Cell Counting kit 8 (CCK-8). We also found that miR-146a inhibited apoptosis of gastric cancer cells by flow cytometry (FCM) and Caspase-Glo® 3/7 assay. Using target prediction algorithms, luciferase reporter assay and Western blot assay, SMAD family member 4 (SMAD4) was identified as a target gene of miR-146a in gastric cancer. Moreover, an inverse correlation was observed between the expression of SMAD4 mRNA and miR-146a in gastric cancer tissues (R=-0.731, P=0.039, Pearson's correlation). Taken together, our results provide important evidence that miR-146a can directly target SMAD4, and suggest that miR-146a may play a role in the development of gastric cancer by modulating cell proliferation and apoptosis. miR-146a could serve as a potential biomarker and therapeutic target against gastric cancer.