Zhang Qian, Yu Song, Huang Xing, Tan Yi, Zhu Cheng, Wang Yan-Ling, Wang Haibin, Lin Hai-Yan, Fu Jiejun, Wang Hongmei
State Key Laboratory of Reproductive BiologyInstitute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of ChinaDepartment of ObstetricsBeijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of ChinaKey Laboratory of Longevity and Ageing-related DiseasesMinistry of Education, Guangxi Medical University, Nanning 530021, People's Republic of ChinaLaboratory Animal CenterChongqing Medical University, Chongqing 400016, People's Republic of ChinaSchool of Life SciencesUniversity of Chinese Academy of Sciences, Beijing 100101, People's Republic of China State Key Laboratory of Reproductive BiologyInstitute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of ChinaDepartment of ObstetricsBeijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of ChinaKey Laboratory of Longevity and Ageing-related DiseasesMinistry of Education, Guangxi Medical University, Nanning 530021, People's Republic of ChinaLaboratory Animal CenterChongqing Medical University, Chongqing 400016, People's Republic of ChinaSchool of Life SciencesUniversity of Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
State Key Laboratory of Reproductive BiologyInstitute of Zoology, Chinese Academy of Sciences, Beijing 100101, People's Republic of ChinaDepartment of ObstetricsBeijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, People's Republic of ChinaKey Laboratory of Longevity and Ageing-related DiseasesMinistry of Education, Guangxi Medical University, Nanning 530021, People's Republic of ChinaLaboratory Animal CenterChongqing Medical University, Chongqing 400016, People's Republic of ChinaSchool of Life SciencesUniversity of Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
Reproduction. 2015 Aug;150(2):139-49. doi: 10.1530/REP-15-0126. Epub 2015 May 28.
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.
Cullin 3（CUL3）是一种支架蛋白，可组装大量泛素连接酶复合物，类似于Skp1-Cullin 1-F盒蛋白复合物。多种遗传模型表明，CUL3对早期胚胎发育至关重要。然而，CUL3在人类滋养层细胞功能中的作用仍不清楚。在本研究中，免疫染色显示CUL3在绒毛细胞滋养层、滋养层柱和侵袭性绒毛外滋养层中强烈表达。沉默CUL3可显著抑制绒毛外植体在体外的生长，并降低滋养层HTR8/SVneo细胞的侵袭和迁移能力。此外，CUL3 siRNA降低了前基质金属蛋白酶9（pro-MMP9）的活性，并增加了金属蛋白酶组织抑制因子1和2（TIMP1和2）的水平。我们还发现，与孕周匹配的对照组相比，子痫前期患者胎盘绒毛中CUL3的水平显著降低。此外，在慢病毒介导的胎盘特异性CUL3基因敲除小鼠中，缺乏CUL3导致母体蜕膜中侵袭性滋养层细胞减少。综上所述，这些结果表明CUL3在滋养层细胞的侵袭和迁移中起重要作用，其表达失调可能与子痫前期的发病有关。
