Hypoxia-induced expression of CXCR4 favors trophoblast cell migration and invasion via the activation of HIF-1α

The placenta initially develops in a low-oxygen environment up to week 8-10 of gestation, and a low oxygen level is a critical factor in the regulation of trophoblast migration and invasion. CXC chemokine receptor 4 (CXCR4) is transcriptionally activated by hypoxia in cancer cells. However, whether CXCR4 is involved in hypoxia-inducible factor (HIF)-1 alpha-dependent trophoblastic migration and invasion in a physiologically hypoxic environment (3% O-2) remains to be fully elucidated and requires further investigation. In the present study, the expression of CXCR4 in first-trimester villi was investigated, as was the response of the trophoblast to hypoxia, and the role of CXCR4 and HIF-1 alpha in trophoblast migration and invasion. CXCR4 was significantly elevated in the first-trimester villi compared with normal full-term placentas. In vitro, the expression of CXCR4 at the mRNA and protein levels was increased in JEG3 cells exposed to 3% O-2 in a time-dependent manner, and the migratory and invasive abilities of the JEG3 cells were upregulated. In addition, CXCR4 knockdown by transfection with CXCR4-specific small interfering (si)RNA decreased the migration and invasion of JEG3 cells exposed to 3% O-2. Furthermore, synthetic siRNA specific for HIF-1 alpha significantly suppressed the expression of CXCR4 in JEG3 cells exposed to 3% O-2, whereas pcDNA-HIF-1 alpha significantly increased the expression of CXCR4. These results indicated that the hypoxia-induced expression of CXCR4 promoted trophoblast cell migration and invasion via the activation of HIF-1 alpha, which is crucial during placentation.