Shochet Gali Epstein, Komemi Oded, Sadeh-Mestechkin Dana, Pomeranz Meir, Fishman Ami, Drucker Liat, Lishner Michael, Matalon Shelly Tartakover
Oncogenetic Laboratory, Meir Medical Centre, 59 Tschernchovski St., 44281, Kfar Saba, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
J Mol Histol. 2016 Dec;47(6):555-563. doi: 10.1007/s10735-016-9699-7. Epub 2016 Oct 6.
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.
在胎盘植入过程中，细胞滋养层细胞分化为绒毛外滋养层（EVT）细胞，这些细胞从胎盘侵入母体子宫血管。热休克蛋白27（HSP27）、信号转导和转录激活因子3（STAT3）以及真核翻译起始因子4E（EIF4E）参与调节EVT细胞的分化/迁移。EIF4E和EIF4G组成翻译起始复合物，这是蛋白质翻译的一个主要控制点。HSP27的分子伴侣特性意味着它直接干扰许多靶蛋白。在肿瘤细胞中发现STAT3、EIF4E和EIF4G是HSP27的客户蛋白。我们旨在分析HSP27是否调节孕早期人胎盘组织中STAT3和EIF4G的水平。我们发现，与STAT3一样，EIF4G在EVT细胞中高表达（免疫组织化学法）。在HTR-8/SVneo细胞（siRNA，EVT细胞系）和胎盘外植体中沉默HSP27可降低STAT3水平（分别降低47%和33%，p<0.05）。在HTR-8/SVneo细胞中，HSP27沉默降低了STAT3磷酸化水平（降低33%，p<0.05）及其靶标（IRF1、MUC1、MMP2/9和EIF4E，降低30 - 49%，p<0.05）。此外，在HTR-8/SVneo细胞和胎盘外植体中，HSP27沉默显著降低了EIF4G水平并提高了其片段水平（p<0.05）。总之，胎盘植入和发育伴随着滋养层细胞的增殖和分化，这需要强烈的蛋白质翻译和STAT3激活。研究发现HSP27是翻译起始和STAT3水平的调节因子。因此，这表明HSP27是胎盘发育和滋养层细胞分化过程中的关键蛋白。
