New insights into the function of Cullin 3 in trophoblast invasion and migration.
New insights into the function of Cullin 3 in trophoblast invasion and migration.
复制标题
DOI：
10.1530/rep-15-0126
复制
发表时间：
2015-08
期刊：
影响因子：
3.8
通讯作者：
Qian Zhang;Song Yu;Xing Huang;Yi Tan;Cheng Zhu;Yan-Ling Wang;Haibin Wang;Hai-yan Lin;
中科院分区：
文献类型：
--
作者：
Qian Zhang;Song Yu;Xing Huang;Yi Tan;Cheng Zhu;Yan-Ling Wang;Haibin Wang;Hai-yan Lin;
Cullin 3（CUL 3）是一种支架蛋白，与Skp 1-Cullin 1-F-box蛋白复合物相似，可形成大量的泛素连接酶复合物。几个遗传模型表明，CUL 3对早期胚胎发育至关重要。然而，CUL 3在人类滋养层功能中的作用仍不清楚。在这项研究中，免疫染色显示，CUL 3强烈表达在绒毛细胞滋养细胞，滋养细胞柱，和浸润绒毛外滋养细胞。CUL 3的沉默显著抑制绒毛外植体的体外生长，并降低滋养层HTR 8/SVneo细胞的侵袭和迁移。此外，CUL 3 siRNA降低pro-MMP 9活性并增加TIMP 1和TIMP 2的水平。我们还发现先兆子痫患者胎盘绒毛中的CUL 3水平与其胎龄匹配的对照组相比显著降低。此外，在慢病毒介导的胎盘特异性CUL 3敲减小鼠中，CUL 3的缺乏导致母体蜕膜中的滋养层细胞侵袭性降低。综上所述，这些结果表明CUL 3在滋养层细胞的侵袭和迁移中起重要作用，其表达失调可能与先兆子痫的发生有关。
Cullin 3 (CUL3), a scaffold protein, assembles a large number of ubiquitin ligase complexes, similar to Skp1-Cullin 1-F-box protein complex. Several genetic models have shown that CUL3 is crucial for early embryonic development. Nevertheless, the role of CUL3 in human trophoblast function remains unclear. In this study, immunostaining revealed that CUL3 was strongly expressed in the villous cytotrophoblasts, the trophoblast column, and the invasive extravillous trophoblasts. Silencing CUL3 significantly inhibited the outgrowth of villous explant ex vivo and decreased invasion and migration of trophoblast HTR8/SVneo cells. Furthermore, CUL3 siRNA decreased pro-MMP9 activity and increased the levels of TIMP1 and 2. We also found that the level of CUL3 in the placental villi from pre-eclamptic patients was significantly lower as compared to that from their gestational age-matched controls. Moreover, in the lentiviral-mediated placenta-specific CUL3 knockdown mice, lack of CUL3 resulted in less invasive trophoblast cells in the maternal decidua. Taken together, these results suggest an essential role for CUL3 in the invasion and migration of trophoblast cells, and dysregulation of its expression may be associated with the onset of pre-eclampsia.