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

Abstract

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...

Correlation between Extracellular Matrix Metalloproteinase Inducer in Peripheral Blood and Serum MMPs in patients with Acute Coronary Syndrome

“…In addition, some studies believe that vulnerable plaque will gradually increase in the late stage of atherosclerosis in some ACS patients, which will promote the increase of MMPs expression level in individual serum, further regulate more inflammatory factors, aggravate the individual inflammatory response, and increase the instability of vulnerable plaque (18)(19)(20). In addition, it has been proposed that the secretion of MMPs by fibroblasts is also affected by EMMPRIN, and the analysis of a large number of inflammatory diseases shows that the overexpression of EMMPRIN can significantly increase the expression level of individual MMPs (21,22). As a kind of chronic inflam-mation, the occurrence of atherosclerosis in patients with ACS is also affected by EMMPRIN, and some studies have found that, under the stimulation of inflammatory factors, the expression of EMMPRIN shows a gradual upward trend, and under this influence, the expression of MMPs in patients' serum also shows a rising trend (23,24).…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…p53 arrests the cell cycle in the G2/M phase by transcriptionally activating 14‐3‐3σ, and plays a role in the response of cells to DNA damage 211,212 . 14‐3‐3‐σ, also known as stratifin, is mainly found in stratified epithelial cells.…”

“…p53 arrests the cell cycle in the G2/M phase by transcriptionally activating 14‐3‐3σ, and plays a role in the response of cells to DNA damage. 211 , 212 14‐3‐3‐σ, also known as stratifin, is mainly found in stratified epithelial cells. 14‐3‐3‐σ, a protein encoded by the SFN gene in humans, is involved in cell cycle checkpoint control after DNA damage.…”

Arnicolide C Suppresses Tumor Progression by Targeting 14-3-3θ in Breast Cancer

“…Studies have shown that 14-3-3 proteins are essential for cancer development [24][25][26][27][28][29]. 14-3-3 proteins are ubiquitously expressed in eukaryotic cells, and there are seven main protein isoforms in mammals [30].…”

“…14-3-3 proteins can bind to other proteins [ 17 , 18 ] and participate in various biological activities, including signal transduction, cell cycle progression, apoptosis, and enzyme activity regulation [ 19 , 20 , 21 , 22 , 23 ]. Studies have shown that 14-3-3 proteins are essential for cancer development [ 24 , 25 , 26 , 27 , 28 , 29 ]. 14-3-3 proteins are ubiquitously expressed in eukaryotic cells, and there are seven main protein isoforms in mammals [ 30 ].…”