Kipkeew Friederike, Kirsch Manuela, Klein Diana, Wuelling Manuela, Winterhager Elke, Gellhaus Alexandra
a Department of Molecular Biology , University of Duisburg-Essen , Essen , Germany.
b Department of Gynecology and Obstetrics , University of Duisburg-Essen , Essen , Germany.
Cell Adh Migr. 2016 Mar 3;10(1-2):163-78. doi: 10.1080/19336918.2016.1139265. Epub 2016 Jan 8.
During placental development, continuous invasion of trophoblasts into the maternal compartment depends on the support of proliferating extravillous trophoblasts (EVTs). Unlike tumor cells, EVTs escape from the cell cycle before invasion into the decidua and spiral arteries. This study focused on the regulation properties of glycosylated and non-glycosylated matricellular CCN1 and CCN3, primarily for proliferation control in the benign SGHPL-5 trophoblast cell line, which originates from the first-trimester placenta. Treating SGHPL-5 trophoblast cells with the glycosylated forms of recombinant CCN1 and CCN3 decreased cell proliferation by bringing about G0/G1 cell cycle arrest, which was accompanied by the upregulation of activated Notch-1 and its target gene p21. Interestingly, both CCN proteins increased senescence-associated β-galactosidase activity and the expression of the senescence marker p16. The migration capability of SGHPL-5 cells was mostly enhanced in response to CCN1 and CCN3, by the activation of FAK and Akt kinase but not by the activation of ERK1/2. In summary, both CCN proteins play a key role in regulating trophoblast cell differentiation by inducing senescence and enhancing migration properties. Reduced levels of CCN1 and CCN3, as found in early-onset preeclampsia, could contribute to a shift from invasive to proliferative EVTs and may explain their shallow invasion properties in this disease.
在胎盘发育过程中，滋养层细胞持续侵入母体组织依赖于增殖的绒毛外滋养层细胞（EVT）的支持。与肿瘤细胞不同，EVT在侵入蜕膜和螺旋动脉之前就脱离了细胞周期。本研究聚焦于糖基化和非糖基化的基质细胞蛋白CCN1和CCN3的调控特性，主要针对源自孕早期胎盘的良性SGHPL-5滋养层细胞系中的增殖控制。用重组CCN1和CCN3的糖基化形式处理SGHPL-5滋养层细胞，通过导致G0/G1期细胞周期停滞来降低细胞增殖，这伴随着活化的Notch-1及其靶基因p21的上调。有趣的是，两种CCN蛋白均增加了衰老相关β-半乳糖苷酶活性和衰老标志物p16的表达。SGHPL-5细胞的迁移能力在响应CCN1和CCN3时大多增强，这是通过FAK和Akt激酶的激活而非ERK1/2的激活实现的。总之，两种CCN蛋白在通过诱导衰老和增强迁移特性来调节滋养层细胞分化中起关键作用。如在早发型子痫前期中发现的CCN1和CCN3水平降低，可能导致从侵入性EVT向增殖性EVT的转变，并可能解释了它们在该疾病中的浅侵入特性。
