Downregulated Kruppel-Like Factor 8 Is Involved in Decreased Trophoblast Invasion Under Hypoxia-Reoxygenation Conditions

Kruppel-like factor 8 (KLF8) is a pivotal transcription factor expressed in the human placenta that can regulate cell invasion. The objective of this study was to assess whether a hypoxia-reoxygenation (H/R) environment affects placental KLF8 expression levels and subcellular localization and to evaluate the relationship between KLF8 levels and trophoblast invasion activity. Human first trimester villous tissues from normal pregnancies and third trimester placentas from pregnancies with or without preeclampsia (PE) were used for the detection of KLF8 expression and correlating its levels with metalloproteinase 9 (MMP-9) expression. In addition, HTR8/SVneo cells were used to mimic the effects of an H/R environment on placentas to study KLF8 expression and trophoblast invasion. The KLF8 levels, MMP-9 levels, and trophoblast invasion were similarly altered; the levels peaked at 8 to 10 weeks of gestation and declined thereafter along with oxygen tension increased from hypoxia to normoxia during early pregnancy, decreased in third trimester placentas from PE pregnancies featured by repeated H/R and HTR8/SVneo cells exposed to H/R compared with the control. Moreover, a visible reduction in KLF8 immunoreactivity was present in the nuclei of cytotrophoblast cells in human villous tissues at 11 weeks, and partial cytoplasmic accumulation of KLF8 was observed in HTR8/SVneo cells treated with H/R. In conclusion, these findings strongly suggest that H/R reduces the expression and nuclear localization of KLF8 to inhibit the trophoblast invasion by downregulating MMP-9 levels. The KLF8 may play a vital role in the pathogenesis of PE as a novel oxygen tension sensor.