HIF-1α and HIF-2α correlate with migration and invasion in gastric cancer

Hypoxia-inducible factor-1 (HIF-1) is a major determinant of invasion and metastasis in several tumor types. We previously reported that HIF-1 alpha contributed to multidrug resistance in gastric cancer. However, the role of HIF-2 alpha on progression of gastric cancer is seldom reported. In this study, we firstly examined the possible role of HIF-1 alpha and HIF-2 alpha in the process of invasiveness and metastasis of gastric cancer, using immunohistochemistry of 80 gastric cancer tissues, western blot and real-time PCR of 8 fresh gastric cancer tissues. The results showed that HIF-1 alpha and HIF-2 alpha significantly correlated with clinical stage and were highly expressed in metastatic gastric cancers compared to nonmetastatic ones. Western blot analysis revealed that hypoxia (1% O-2, 8 h) induced HIF-1 alpha and HIF-2 alpha expression in different gastric cancer cell lines, including SGC7901, AGS, MGC803 and MKN45. Adhesion and invasion assays found that hypoxia caused an increase in adhesive and invasive abilities of gastric cancer cells. Small interfering (si) RNA against HIF-1 alpha and HIF-2 alpha in SGC7901 cells significantly inhibited hypoxia-induced adhesive and invasive abilities. Finally, the JNK inhibitor SP600125 abolished hypoxia-induced HIF-1 alpha and HIF-2 alpha expression, and inhibited the adhesive and invasive abilities of gastric cancer cells exposed to hypoxia in a dose-dependent manner. Taken together, the present work suggested that HIF-1 alpha and HIF-2 alpha were involved in metastasis and invasion of gastric cancer cells under hypoxia, with the involvement of JNK signal pathway.