We previously demonstrated that hypoxia increased the hypoxia-inducible factor (HIF-1)-dependent MGr1-Ag/37LRP expression, which enhanced adhesion of gastric cancer cells to laminin, inhibited drug-induced apoptosis and caused cell adhesion-mediated drug resistance (CAM-DR). Here, we investigated the role of extracellular-regulated kinase (ERK) 1/2 in the signaling mechanisms underlying these events. We found that hypoxia activated ERK activity in vitro and in vivo. Overexpression of mitogen-activated protein kinase (MAPK) kinase (MEK), which preferentially activated ERK, mimics, in a nonadditive way, hypoxia-induced activity of MGr1-Ag/37LRP promoter and expression of MGr1-Ag/37LRP. Furthermore, U0126, the MEK inhibitor, inhibited hypoxia- and MEK-induced MGr1-Ag/37LRP promoter activity in a dose-dependent manner. MEK inhibition also reversed hypoxia- and MEK-induced HIF-1 protein and its activity in a dose-dependent manner. We also investigated reactive oxygen species signaling this response. Exogenous addition of H(2)O(2) was sufficient to activate ERK in a dose-dependent profile. Reactive oxygen species scavengers of H(2)O(2) significantly inhibited hypoxia-induced ERK or HIF-1 activation and sequential expression of MGr1-Ag/37LRP. We also investigated the signaling in hypoxia-induced cell adhesion and apoptosis induced by vincristine. Hypoxia significantly enhanced adhesion of SGC7901 cells to laminin in a time-dependent manner, which might be inhibited by the MEK inhibitor U0126 and MGr1-Ag/37LRP siRNA. Consistent with results of adhesion assay, hypoxia-resistant apoptosis might be reversed by U0126 in a dose-dependent manner. Our results suggest that hypoxia-elicited MGr1-Ag/37LRP expression activated by HIF-1 depends on ERK activation. These events are dependent of reactive oxygen intermediates.