The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas

Abstract

Ovarian epithelial carcinomas (OECs) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In our study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression. Published 2008 Wiley-Liss, Inc. This article is a U.S. Government work, and, as such, is in the public domain in the United States of America.Key words: ovarian cancer; ZNF217; EEF1A2; oncogene; ovarian epithelial cells; neoplastic progressionThe transcription factor ZNF217 and the eukaryotic translation elongation factor EEF1A2 are both located on chromosome 20q13, a locus which is frequently amplified in ovarian epithelial carcinomas. There is both clinical and experimental evidence that these 2 proteins act as oncogenes in ovarian carcinogenesis as well as in other forms of cancer. However, because of the coexistence of multiple putative oncogenes on chromosome 20q, it has been difficult to define their individual specific influence on malignant progression.20q13 amplification and overexpression of ZNF217 have been described in many types of human cancers, including ovarian carcinomas. 1,2 Recent evidence indicates that ZNF217 is a transcriptional repressor 3,4 and that it may contribute to neoplastic progression by attenuating apoptotic signals. 5,6 In experimental systems, overexpression of ZNF217 has been shown to immortalize cell lines with limited life spans, such as human mammary epithelial cell lines and SV40 Tag/tag transduced ovarian surface epithelial cells (IOSE cells). In both of these cell types, ZNF217 increased telomerase activity and stabilized telomere lengths. 7,8 ZNF217-transduced IOSE cells also acquired anchorage ind...

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