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-1α contributed to multidrug resistance in gastric cancer. However, the role of HIF-2α on the progression of gastric cancer is seldom reported. In this study, we first examined the possible role of HIF-1α and HIF-2α 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-1α and HIF-2α were significantly correlated with the clinical stage and were highly expressed in metastatic gastric cancers compared to nonmetastatic ones. Western blot analysis revealed that hypoxia (1% O₂, 8 h) induced HIF-1α and HIF-2α 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-1α and HIF-2α in SGC7901 cells significantly inhibited hypoxia-induced adhesive and invasive abilities. Finally, the JNK inhibitor SP 600125 abolished hypoxia-induced HIF-1α and HIF-2α 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-1α and HIF-2α were involved in metastasis and invasion of gastric cancer cells under hypoxia, with the involvement of JNK signal pathway.
Wang
Yanxia
Y
Department of Pathology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
Li
Zhichao
Z
Zhang
Hongbo
H
Jin
Haifeng
H
Sun
Li
L
Dong
Haiying
H
Xu
Min
M
Zhao
Pengtao
P
Zhang
Bo
B
Wang
Jin
J
Pan
Yanglin
Y
Liu
Lili
L
D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002448:Cell Adhesion; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051793:Hypoxia-Inducible Factor 1; D048031:JNK Mitogen-Activated Protein Kinases; D034741:RNA, Small Interfering; D000099162:Endothelial PAS Domain-Containing Protein 1