Placental implantation is essential for fetal growth. Main players in placental implantation are extravillous-trophoblast (EVT) cells that invade from the villous to the uterine and remodel fetoplacental vasculature. Similarities exist between the implantation mechanisms of EVT and tumor cells. Both share the same biochemical mediators including MMP9 and VEGF. The level of these targets is regulated by the protein-translation-initiation-factor-4E (eIF4E). Cancer cells have elevated eIF4E and they are vulnerable to its silencing. Based on these similarities we speculated that EVT function is highly dependent on eIF4E.
Objective: Analyzing the involvement of eIF4E in placental implantation.
Methods: EIF4E levels were assessed in first trimester human placenta (IHC) and in placental explants before and after EVT differentiation (western-blotting). We evaluated the effect of eIF4E knockdown (siRNA) on the phenotype of EVT cell line, HTR8. Parameters tested included eIF4E and its targets’ levels (cMyc, cyclin-D1; western-blotting), migration (scratch-assay), death (Annexin/7AAD, flow-cytometry (FACS), cell-cycle (PI, FACS), MMP9, (zymogram) and VEGF (ELISA).
Results: High eIF4E levels were found in EVT cells in comparison to other placental cells. Furthermore, silencing eIF4E modestly elevated cell-death (~10%) a slight G1 cell-cycle arrest (~6%) and dramatically reduced HTR8 cell migration (~45%), MMP9 activity (~35%) and VEGF secretion (45%) all critical for placental implantation.
Conclusions: It was reported that preeclampsia involves impaired placental implantation and abnormal translation initiation. Our results suggest that EVT implantation is highly dependent on eIF4E. Based on these data we suggest that eIF4E activity may be impaired in early placentae of preeclamptic women.
Kitroser E, Pomeranz M, Fishman A, Epstein Shochet G, Drucker L, Dana Sade, Lishner M,
Oncogenetic Laboratory, Meir Medical Center, Kfar Saba, Israel