This study was conducted to investigate the biological role of periostin in gastric cancer (GC) under hypoxia. Western blot analysis revealed that along with an upregulation of hypoxia-inducible factor-1alpha, there was a time-dependent induction of periostin in MKN-45 cells under hypoxia (2% O-2), increasing by eightfold as compared to normoxic cells. Pretreatment with 30 mu M PD98059, an inhibitor of ERK1/2, significantly reduced hypoxia-stimulated periostin expression (P < 0.01). Periostin knockdown in MKN-45 cells was achieved by specific small interfering RNA (siRNA). The conditioned medium from periostin siRNA-transfected MKN-45 cells induced significantly less (P < 0.01) endothelial tube formation than control siRNA-transfected cells. Additionally, periostin silencing markedly decreased the mRNA expression and secretion of vascular endothelial growth factor (VEGF) in hypoxic MKN-45 cells. Thus, our data suggest that periostin is a hypoxia-response gene and mediates a cross talk between GC and endothelial cells under hypoxia, partially through regulation of the VEGF expression. (c) 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:364-369, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/jbt.21498