title: Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/β-catenin signaling.
abstract: Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecological malignancies owing to poor screening methods, non-specific symptoms and limited knowledge of the cellular targets that contribute to the disease. Cyclin G2 is an unconventional cyclin that acts to oppose cell cycle progression. Dysregulation of the cyclin G2 gene (CCNG2) in a variety of human cancers has been reported; however, the role of cyclin G2 in tumorigenesis remains unclear. In this study, we investigated the function of cyclin G2 in EOC. In vitro and in vivo studies using several EOC-derived tumor cell lines revealed that cyclin G2 inhibited cell proliferation, migration, invasion and spheroid formation, as well as tumor formation and invasion. By interrogating cDNA microarray data sets, we found that CCGN2 mRNA is reduced in several large cohorts of human ovarian carcinoma when compared with normal ovarian surface epithelium or borderline tumors of the ovary. Mechanistically, cyclin G2 was found to suppress epithelial-to-mesenchymal transition (EMT), as demonstrated by the differential regulation of various EMT genes, such as Snail, Slug, vimentin and E-cadherin. Moreover, cyclin G2 potently suppressed the Wnt/β-catenin signaling pathway by downregulating key Wnt components, namely LRP6, DVL2 and β-catenin, which could be linked to inhibition of EMT. Taken together, our novel findings demonstrate that cyclin G2 has potent tumor-suppressive effects in EOCs by inhibiting EMT through attenuating Wnt/β-catenin signaling.
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Bernaudo
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Salem
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Rosman
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Ye
authors.affiliation: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: B B
authors.initials: BB
authors.lastname: Yang
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Vanderhyden
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.|Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Peng
mesh_terms: D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D000077216:Carcinoma, Ovarian Epithelial; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D056767:Cyclin G2 / Q000235:genetics*; D000072261:Dishevelled Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000037:antagonists & inhibitors / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D056767:Cyclin G2; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051176:beta Catenin