title: Heat shock protein-27 (HSP27) regulates STAT3 and eIF4G levels in first trimester human placenta.
abstract: During placental implantation, cytotrophoblast cells differentiate to extravillous trophoblast (EVT) cells that invade from the placenta into the maternal uterine blood vessels. The heat shock protein-27 (HSP27), the signal transducer and activator of transcription-3 (STAT3) and the eukaryotic translation initiation factor 4E (EIF4E) are involved in regulating EVT cell differentiation/migration. EIF4E and EIF4G compose the translation initiation complex, which is a major control point in protein translation. The molecular chaperone distinctiveness of HSP27 implies that it directly interferes with many target proteins. STAT3, EIF4E, and EIF4G were found to be HSP27 client proteins in tumor cells. We aimed to analyze if HSP27 regulate STAT3 and EIF4G levels in first trimester human placenta. We found that like STAT3, EIF4G is highly expressed in the EVT cells (immunohistochemistry). Silencing HSP27 in HTR-8/SVneo cells (siRNA, EVT cell line) and in placental explants reduced STAT3 level (47 and 33 %, respectively, p < 0.05). HSP27 silencing reduced the levels of STAT3 phosphorylation (33 % reduction, p < 0.05) and targets (IRF1, MUC1, MMP2/9 and EIF4E, 30-49 % reduction, p < 0.05) in the HTR-8/SVneo cells. Moreover, HSP27 silencing significantly reduced EIF4G level and elevated the level of its fragments in HTR-8/SVneo cells and in the placental explants (p < 0.05). In conclusion, Placental implantation and development are accompanied by trophoblast cell proliferation and differentiation, which necessitates intense protein translation and STAT3 activation. HSP27 was found to be regulator of translation initiation and STAT3 level. Therefore, it suggests that HSP27 is a key protein during placental development and trophoblast cell differentiation.
authors.affiliation: Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Gali Epstein
authors.identifier: http://orcid.org/0000-0002-3417-9171
authors.initials: GE
authors.lastname: Shochet
authors.affiliation: Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Komemi
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Obstetrics and Gynecology, Meir Medical Centre, 44281, Kfar Saba, Israel.
authors.forename: Dana
authors.initials: D
authors.lastname: Sadeh-Mestechkin
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Obstetrics and Gynecology, Meir Medical Centre, 44281, Kfar Saba, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Pomeranz
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Obstetrics and Gynecology, Meir Medical Centre, 44281, Kfar Saba, Israel.
authors.forename: Ami
authors.initials: A
authors.lastname: Fishman
authors.affiliation: Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Drucker
authors.affiliation: Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Department of Internal Medicine A, Meir Medical Centre, 44281, Kfar Saba, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Lishner
authors.affiliation: Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel. matalon.shelly@clalit.org.il.|Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. matalon.shelly@clalit.org.il.
authors.forename: Shelly Tartakover
authors.initials: ST
authors.lastname: Matalon
mesh_terms: D015415:Biomarkers; D002460:Cell Line; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D015415:Biomarkers; D039603:Eukaryotic Initiation Factor-4G; D055551:HSP27 Heat-Shock Proteins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor
keywords: Eukaryotic translation initiation factor 4G; Extravillous trophoblast; Heat shock protein-27; Placenta; STAT3