Emerging tasks of PAR₁ and PAR₂ in the placenta trophoblast anchoring to the uterus deciduas

Human fetal development depends on the ability of the embryo to gain access to maternal circulation. To accomplish this task, trophoblasts, the specialized stem cells of the newly formed placenta, invade the uterus during the first trimester of pregnancy, and remodel the extracellular matrix microenvironment to acheive firm anchorage of the placenta to the uterus decidua. While trophoblast invasion shares many features with tumor cell invasion, it is dissimilar by its strictly spatial and temporally regulated control. Despite extensive efforts toward the elucidation of the molecular pathway controlling cytotrophoblast (CTB) invasion, it remains poorly defined. There are striking resemblances between tumor cell invasion and cytotrophoblast implantation to the deciduas where the role of protease-activated-receptors (PARs) and Wnt signaling is well recognized. PAR₁ and PAR₂, the first two members of the PAR family, are emerging with central assignments in tumor biology. Likewise, a high expression level of PAR₁ was observed in the cytotrophoblast cells of complete hydatidiform mole as compared to minimal levels seen in normal age-matched placenta. We examined the modulation of PAR₁ and PAR₂ expression and function in CTB invasion and beta-catenin stabilization. Toward this end, we utilized a model system of extravillous trophoblast (EVT) organ culture and various placenta cell lines (e.g., JAR and HTR-8/Svneo). Activation of PAR₁ induced EVT invasion while hPAR1-siRNA silencing or application of the PAR₁ antagonist SCH79797-effectively inhibited invasion. Nuclear localization of beta-catenin is seen only after PAR₁ activation, and is markedly reduced regardless of whether hPAR1-siRNA construct or PAR₁ antagonist was used. Enforced expression of the Wnt antagonists, Secreted Frizzled Related Proteins, SFRP2and5, into HTR-8/Svneo, a transformed placenta cell-line, resulted in markedly lower nuclear beta-catenin levels, similar to the effect obtained by hPAR1-siRNA treatment. Identification of PAR_{1and 2} downstream target/s may nonetheless contribute to the formation of a future platform system for eliciting firm placenta-uterus interactions and for a better definition of late pregnancy outcomes.