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.