title: New insights into the function of Cullin 3 in trophoblast invasion and migration.
abstract: 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.
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Song
authors.initials: S
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Xing
authors.initials: X
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Haibin
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Lin
authors.affiliation: 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 wanghm@ioz.ac.cn fujiejun@126.com.
authors.forename: Jiejun
authors.initials: J
authors.lastname: Fu
authors.affiliation: 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 wanghm@ioz.ac.cn fujiejun@126.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D044842:Cullin Proteins / Q000235:genetics* / Q000502:physiology*; D003656:Decidua / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D011225:Pre-Eclampsia / Q000235:genetics / Q000503:physiopathology; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D014327:Trophoblasts / Q000502:physiology*; D014945:Wound Healing / Q000187:drug effects
chemical_list: C503645:CUL3 protein, human; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020780:Matrix Metalloproteinase 9