CUL1 promotes trophoblast cell invasion at the maternal-fetal interface.
CUL1 promotes trophoblast cell invasion at the maternal-fetal interface.
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DOI：
10.1038/cddis.2013.1
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发表时间：
2013-02-21
影响因子：
9
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中科院分区：
文献类型：
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人滋养层祖细胞通过两种不同的途径分化，成为高度侵袭性的绒毛外细胞滋养层（CTB）细胞（EVT）或融合形成合胞体滋养层。滋养层分化不足导致胎盘灌注不良，甚至并发症，如先兆子痫（PE）。Cullin 1（CUL 1）是一种基于Cullin的泛素连接酶的支架蛋白，在早期胚胎发育中起重要作用。然而，CUL 1在胎盘发育过程中滋养层分化中的作用尚未研究。在这里，我们表明，CUL 1的表达在CTB细胞和EVT在第一个三个月的人胎盘的免疫组织化学。CUL 1 siRNA在体外显著抑制绒毛外外植体的生长，以及EVT来源的HTR 8/SVneo细胞的侵袭和迁移。这种抑制伴随着基质金属蛋白酶（MMP）-9的明胶分解活性降低和MMP的组织抑制剂（TIMP-1和-2）的表达增加。外源性CUL 1促进HTR 8/SVneo细胞的侵袭和迁移。值得注意的是，CUL 1在滋养层合胞过程中逐渐减少，CUL 1 siRNA显著增强毛喉素诱导的绒毛膜癌BeWo细胞融合。人先兆子痫胎盘绒毛中的CUL 1蛋白水平显著低于其匹配的对照胎盘。综上所述，我们的研究结果表明，CUL 1促进人类滋养层细胞的侵袭和失调的CUL 1表达可能与PE。
Human trophoblast progenitor cells differentiate via two distinct pathways, to become the highly invasive extravillous cytotrophoblast (CTB) cells (EVT) or fuse to form syncytiotrophoblast. Inadequate trophoblast differentiation results in poor placenta perfusion, or even complications such as pre-eclampsia (PE). Cullin1 (CUL1), a scaffold protein in cullin-based ubiquitin ligases, plays an important role in early embryonic development. However, the role of CUL1 in trophoblast differentiation during placenta development has not been examined. Here we show that CUL1 was expressed in CTB cells and EVT in the first trimester human placentas by immunohistochemistry. CUL1 siRNA significantly inhibited outgrowth of extravillous explants in vitro, as well as invasion and migration of HTR8/SVneo cells of EVT origin. This inhibition was accompanied by decreased gelatinolytic activities of matrix metalloproteinase (MMP)-9 and increased expression of tissue inhibitors of MMPs (TIMP-1 and -2). Consistently, exogenous CUL1 promoted invasion and migration of HTR8/SVneo cells. Notably, CUL1 was gradually decreased during trophoblast syncytialization and CUL1 siRNA significantly enhanced forskolin-induced fusion of choriocarcinoma BeWo cells. CUL1 protein levels in human pre-eclamptic placental villi were significantly lower as compared to their matched control placentas. Taken together, our results suggest that CUL1 promotes human trophoblast cell invasion and dysregulation of CUL1 expression may be associated with PE.