Background/Aim: The 14-3-3 protein family has a variety of functions in cellular responses in different organisms, including cell-cycle regulation, apoptosis, and malignant transformation. induces G2 arrest, which enables repair of damaged DNA. The purpose of this study was to identify the role of 14-3-3σ up-regulation by hepatocyte growth factor (HGF) in cancer cell proliferation and invasion in gastric cancer. Materials and Methods: In this study, cell culture, western blotting, real-time polymerase chain reaction, zymography, 14-3-3σ knock-down using short hairpin RNA (shRNA), electrophoresis mobility-shift assay, chromatin immunoprecipitation assay and standard two-chamber invasion assay were applied. Results: Firstly, we confirmed that the expression of 14-3-3σ in gastric cancer cells was up-regulated by HGF. To identify how HGF-induced 14-3-3σ expression affects matrix metalloproteinase-1 (MMP1) expression, the cells were treated with the mitogen-activated protein kinase kinase inhibitor PD098059 and analyzed using western blotting. The HGF-mediated expression of MMP1 protein decreased in the presence of PD098059. The role of 14-3-3σ in MMP1 expression was determined through 14-3-3σ knockdown using shRNA. 14-3-3σ-shRNA cells showed reduced levels of MMP1, phosphorylated extracellular signalregulated kinase, and pp38. HGF-mediated cell proliferation and in vitro invasion were reduced in 14-3-3σ knockdown cells. Serum 14-3-3σ levels were also significantly reduced following gastrectomy in patients with stage II or stage III gastric cancer (p<0.05). Conclusion: These results suggest that 14-3-3σ plays an important role in cell proliferation and metastasis in gastric cancer, and 14-3-3σ may be a novel target for detection and prevention of progression of gastric cancer. In addition, the serum 14-3-3σ level is associated with treatment status in patients with locally advanced gastric cancer.The HGF and MET proto-oncogene, receptor tyrosine kinase (MET) pathways play an important role not only in normal cell development but also in the pathogenesis of most types of human cancer (1-4). To explain the effects of HGF on the pathogenesis of gastric cancer, the gastric adenocarcinoma cell lines, NUGC3 and MKN-28, were screened using a human complementary DNA (cDNA) microarray in previous work, and many genes that are regulated by HGF were identified (5). That study suggested that calpain 12, cold-shock domain protein A, 14-3-3 proteins, cervical cancer 1 proto-oncogene, gastrin-releasing peptide, hepatoma-derived growth factor, mitogen-activated protein-binding protein-interacting protein and S100 calcium-binding protein A11 were up-regulated threefold or higher after treatment with HGF (2, 6).The 14-3-3 proteins are a large family of small, acidic polypeptides of 28-33 kDa that are encoded by at least two different 14-3-3 genes in all eukaryotic species (7, 8). 14-3-3 Proteins are an important family for research because they have diverse cellular roles in signal transduction involved in cancer development, includin...