The unfolded protein response potentiates epithelial-to-mesenchymal transition (EMT) of gastric cancer cells under severe hypoxic conditions

The hypoxic condition occurs in most types of solid tumors and has been shown to be associated with the metastatic ability of gastric cancer. A previous study has demonstrated that hypoxia might stimulate epithelial-to-mesenchymal transition (EMT) of gastric cancer cells. Nevertheless, the mechanism has not yet been completely understood. In the current study, the human gastric cancer cell lines HGC27 and MGC803 were presented to normoxic (21 % O₂), hypoxic (1 % O₂) or severe hypoxic (0.1 % O₂) conditions for 24 h. We found that hypoxia exposure induced EMT of gastric cancer cells, which was promoted by severe hypoxia condition. Meanwhile, expressions of PERK, ATF4 and ATF6 proteins were elevated in cells under conditions of severe hypoxia but not by normoxia or hypoxia. Knockdown of PERK, ATF4 or ATF6 impeded EMT of gastric cancer cells induced by severe hypoxia. Furthermore, severe hypoxia exposure extremely boosted the expression of TGF-β, which was blocked by the knockdown of PERK, ATF4 or ATF6 expression. Additionally, we found that TGF-β release caused by hypoxia is facilitated by elevated UPR proteins and led to the activation of Smad2/3 and PI3K/Akt signaling. Our data suggest that UPR potentiates the EMT of gastric cancer cells under conditions of severe hypoxia.