14-3-3 Sigma Protein Contributes to Hepatocyte Growth Factor-mediated Cell Proliferation and Invasion Matrix Metalloproteinase-1 Regulation in Human Gastric Cancer.

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. 14-3-3 Sigma protein (14-3-3σ) 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 signal-regulated 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.