title: FBI-1 Is Overexpressed in Gestational Trophoblastic Disease and Promotes Tumor Growth and Cell Aggressiveness of Choriocarcinoma via PI3K/Akt Signaling.
abstract: Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts.
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Victor C Y
authors.initials: VC
authors.lastname: Mak
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Oscar G W
authors.initials: OG
authors.lastname: Wong
authors.affiliation: Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong, China.
authors.forename: Michelle K Y
authors.initials: MK
authors.lastname: Siu
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Esther S Y
authors.initials: ES
authors.lastname: Wong
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Wai-Yan
authors.initials: WY
authors.lastname: Ng
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Richard W C
authors.initials: RW
authors.lastname: Wong
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China.
authors.forename: Ka-Kui
authors.initials: KK
authors.lastname: Chan
authors.affiliation: Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong, China.
authors.forename: Hextan Y S
authors.initials: HY
authors.lastname: Ngan
authors.affiliation: Department of Pathology, University of Hong Kong, Hong Kong, China. Electronic address: anycheun@hkucc.hku.hk.
authors.forename: Annie N Y
authors.initials: AN
authors.lastname: Cheung
mesh_terms: D000818:Animals; D000906:Antibodies; D017209:Apoptosis; D015197:Carcinogenicity Tests; D002465:Cell Movement; D002822:Choriocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D031901:Gestational Trophoblastic Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011817:Rabbits; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C485514:ZBTB7A protein, human; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt