Ubiquitin Ligase Cullin 7 Induces Epithelial-Mesenchymal Transition in Human Choriocarcinoma Cells*

• Published in: Journal of Biological Chemistry
• Main Authors: Fu, Jiejun, Lv, Xiaoyin, Lin, Haiyan, Wu, Liang, Wang, Rui, Zhou, Zhi, Zhang, Baohua, Wang, Yan-Ling, Tsang, Benjamin K., Zhu, Cheng, Wang, Hongmei
• Format: Text
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 2010
• Subjects: Cell Biology; Yakuts
• Online Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856293; http://www.ncbi.nlm.nih.gov/pubmed/20139075; https://doi.org/10.1074/jbc.M109.004200

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.