Ubiquitin ligase cullin 7 induces epithelial-mesenchymal transition in human choriocarcinoma cells.
Germ line mutations of the ubiquitin ligase cullin 7 (CUL7) are linked to 3-M syndrome and Yakuts short stature syndrome, both of which are characterized by pre- and post-natal growth retardation. CUL7 knock-out mice show placental and embryonic defects similar to intrauterine growth retardation, suggesting a role of CUL7 in placentation. CUL7 was found in this study to be highly expressed in first trimester invasive human placental villi as well as in HTR8/SVneo and B6Tert cells, two cell lines derived from human first trimester trophoblast cells. However, CUL7 levels in term trophoblast cells or JEG-3 cells, which are derived from human choriocarcinoma but exhibit weak invasion capacity, were low or undetectable. Forced expression of CUL7 in JEG-3 cells induced cell morphological changes characteristic of epithelial-mesenchymal transition, which was accompanied by a complete loss of the epithelial markers E-cadherin and P-cadherin and a significant elevation of mesenchymal markers Vimentin and N-cadherin. JEG-3 cells expressing CUL7 exhibited enhanced cell migration and invasion. Conversely, CUL7-specific RNA interference in HTR8/SVneo cells resulted in increased E-cadherin expression and reduced cell migration and invasion. Furthermore, CUL7 expression down-regulated E-cadherin mRNA expression by up-regulating ZEB1 and Slug, two transcriptional repressors of E-cadherin. Finally, CUL7-induced loss of E-cadherin expression was partially reversed by treatment of CUL7-expressing cells with the proteasome inhibitor MG-132. These results suggest that the CUL7 E3 ligase is a key regulator in trophoblast cell epithelial-mesenchymal transition and placental development.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China. wanghm@ioz.ac.cn
Jiejun
J
Fu
Xiaoyin
X
Lv
Haiyan
H
Lin
Liang
L
Wu
Rui
R
Wang
Zhi
Z
Zhou
Baohua
B
Zhang
Yan-Ling
YL
Wang
Benjamin K
BK
Tsang
Cheng
C
Zhu
Hongmei
H
Wang
D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000201:enzymology* / Q000473:pathology*; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008648:Mesoderm / Q000201:enzymology / Q000473:pathology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology*; D000071799:Zinc Finger E-box-Binding Homeobox 1
C506299:CUL7 protein, human; D015820:Cadherins; D044842:Cullin Proteins; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1