CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties
CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties
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DOI：
10.1080/19336918.2016.1139265
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发表时间：
2016-01
影响因子：
3.2
通讯作者：
Friederike Kipkeew;Manuela Kirsch;D. Klein;M. Wuelling;E. Winterhager;A. Gellhaus
中科院分区：
文献类型：
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作者：
Friederike Kipkeew;Manuela Kirsch;D. Klein;M. Wuelling;E. Winterhager;A. Gellhaus
摘要在胎盘发育过程中，滋养细胞的持续侵入依赖于增殖的绒毛外滋养细胞(EVT)的支持。与肿瘤细胞不同，EVT在侵入蜕膜和螺旋动脉之前逃离细胞周期。本研究主要研究糖基化和非糖基化基质细胞CCN1和CCN3的调控特性，主要用于良性SGHPL-5滋养层细胞系的增殖控制。糖基化的重组CCN1和CCN3作用于SGHPL-5滋养层细胞，使细胞周期停滞于G0/G1期，从而抑制细胞增殖，并伴随着激活的Notch-1及其靶基因p21的上调。有趣的是，这两种CCN蛋白都增加了衰老相关的β-半乳糖苷酶活性和衰老标记p16的表达。SGHPL-5细胞的迁移能力主要受CCN1和CCN3、FAK和Akt激酶的激活而不是ERK1/2的激活而增强。综上所述，这两种CCN蛋白都通过诱导衰老和增强迁移特性来调节滋养层细胞的分化。在早发性子痫前期中发现的CCN1和CCN3水平降低，可能有助于从侵袭性EVT向增生性EVT的转变，并可能解释它们在这种疾病中的浅表侵袭特性。
ABSTRACT 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.