Asparaginyl endopeptidase (AEP) is a lysosomal protease and overexpressive in gastric cancer. AEP was higher expressive in peritoneal metastatic loci than that in primary gastric cancer. Then we overexpressed AEP or knocked it down with a lentiviral vector in gastric cancer cell lines and detected the cell cycle arrest and the changes of the invasive and metastatic ability in vitro and in vivo. When AEP was knocked-down, the proliferative, invasive and metastatic capacity of gastric cancer cells were inhibited, and the population of sub-G1 cells increased. The expressive level of twist, which is a transcriptional factor, decreased significantly, and the epithelial markers' expression of EMT, E-cadherin increased, but that of the mesenchymal markers, N-cadherin, β-catenin and Vimentin decreased, if AEP was knocked down. These results showed that AEP could promote invasion and metastasis by modulating EMT. We used phosphorylation-specific antibody microarrays to investigate the mechanism that AEP promotes gastric cancer invasion and metastasis, and found that the phosphorylation level of AKT and MAPK signaling pathways were decreased significantly if AEP was knocked-down. Therefore, AKT and MAPK signaling pathways took part in the modulation.
Keywords: asparaginyl endopeptidase; epithelial-to-mesenchymal transition; gastric cancer; metastasis; signaling pathway.