title: Multiple roles of the candidate oncogene ZNF217 in ovarian epithelial neoplastic progression.
abstract: The transcription factor ZNF217 is often amplified in ovarian cancer, but its role in neoplastic progression is unknown. We introduced ZNF217-HA by adenoviral and retroviral infection into normal human ovarian surface epithelial cells (OSE), i.e., the source of ovarian cancer, and into SV40 Tag/tag expressing, p53/pRB-deficient OSE with extended but finite life spans (IOSE). In OSE, ZNF217-HA reduced cell-substratum adhesion and accelerated loss of senescent cells, but caused no obvious proneoplastic changes. In contrast, ZNF217-HA transduction into IOSE yielded two permanent lines, I-80RZ and I-144RZ, which exhibited telomerase activity, stable telomere lengths, anchorage independence and reduced serum dependence, but were not tumorigenic in SCID mice. This immortalization required short-term EGF treatment near the time of crisis. The permanent lines were EGF-independent, but ZNF217-dependent since siRNA to ZNF217 inhibited anchorage independence and arrested growth. Array CGH revealed genomic changes resembling those of ovarian carcinomas, such as amplicons at 3q and 20q, and deletions at 4q and 18, associated with underexpressed annexin A10, N-cadherin, desmocollin 3 and PAI-2, which have been reported as tumor suppressors. The lines overexpressed EEF1A2, SMARA3 and STAT1 and underexpressed other oncogenes, tumor suppressors and extracellular matrix/adhesion genes. The results implicate ZNF217 as an ovarian oncogene, which is detrimental to senescing normal OSE cells but contributes to neoplastic progression in OSE with inactivated p53/RB. The resemblance of the genomic changes in the ZNF217-overexpressing lines to ovarian carcinomas provides a unique model to investigate interrelationships between these changes and ovarian neoplastic phenotypes.
authors.affiliation: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Li
authors.forename: Sarah
authors.initials: S
authors.lastname: Maines-Bandiera
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Kuo
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Guan
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.forename: Mark
authors.initials: M
authors.lastname: Hills
authors.forename: Guiqing
authors.initials: G
authors.lastname: Huang
authors.forename: Collin C
authors.initials: CC
authors.lastname: Collins
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Nelly
authors.initials: N
authors.lastname: Auersperg
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D010051:Ovarian Neoplasms / Q000209:etiology* / Q000473:pathology; D010641:Phenotype; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
chemical_list: D015534:Trans-Activators; C113698:ZNF217 protein, human; D004815:Epidermal Growth Factor; D006854:Hydrocortisone