title: The involvement of eukaryotic translation initiation factor 4E in extravillous trophoblast cell function.
abstract: Extravillous trophoblast cells (EVT) are major players in placental implantation. They differentiate in the villous cell column, invade to the uterus and remodel the uterine spiral arteries. Trophoblast and tumor cells have similar invasion mechanisms, share similar biochemical mediators (e.g. c-myc, MMP9) and growth-factors (e.g. VEGF). The mRNA of these proteins has extremely structured 5-UTR and their translation is highly dependent on eukaryotic-translation-initiation-factor-4E (eIF4E). Cancer cells have elevated eIF4E and are more vulnerable to its silencing than normal cells. We speculated that like cancer, trophoblast function is highly eIF4E dependent.
  
  
  OBJECTIVE
  Analyze eIF4E involvement in EVT differentiation and function.
  
  
  METHODS
  EIF4E levels were assessed in first-trimester human placentae and in placental explants before and after EVT differentiation. The effect of eIF4E knockdown (siRNA, ribavirin) on the phenotype of placental explant and EVT cell lines (HTR-8/SVNEO) was evaluated. Tested parameters included eIF4E and its target levels, migration, invasion, cell death, cell cycle and cell count.
  
  
  RESULTS
  High eIF4E levels were found in cytotrophoblast and especially EVT cells during their differentiation in the villi, compared to other placental cell types. EIF4E silencing increased cell death and cell cycle arrest in placental explants and HTR-8/SVNEO cells. Although it induced EVT outgrowth in the placental explants, it reduced HTR-8/SVNEO motility, reflecting the importance of using ex vivo models that include an intact placental microenvironment in its original architecture.
  
  
  CONCLUSIONS
  Our results suggest that eIF4E prevents final EVT differentiation and supports placental cell proliferation and survival. A balance between cell proliferation and differentiation is crucial for placental development and implantation.
authors: Oncogenetic Laboratory, Meir Medical Center, Kfar Saba 44281, Israel.
authors: E
authors: E
authors: Kitroser
authors: M
authors: M
authors: Pomeranz
authors: G
authors: G
authors: Epstein Shochet
authors: A
authors: A
authors: Fishman
authors: L
authors: L
authors: Drucker
authors: D
authors: D
authors: Sadeh-Mestechkin
authors: M
authors: M
authors: Lishner
authors: S
authors: S
authors: Tartakover-Matalon
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D039561:Eukaryotic Initiation Factor-4E / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D005260:Female; D006801:Humans; D010920:Placenta / Q000737:chemistry / Q000187:drug effects; D010929:Placentation / Q000502:physiology; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D034741:RNA, Small Interfering / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D046509:Tissue Culture Techniques; D014327:Trophoblasts / Q000502:physiology*
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D034741:RNA, Small Interfering; D012254:Ribavirin