Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

Tomlinson, V A L; Newbery, Helen; Bergmann, Jan H.; Boyd, J. Brian; Scott, Derek Anthony; Wray, Naomi R.; Sellar, Grant C.; Gabra, Hani; Graham, Andrea; Williams, Alistair; Abbott, Catherine M.

doi:10.1038/sj.bjc.6603748

Cited by 40 publications

(37 citation statements)

References 18 publications

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“…Analysis of the expression profiles using Significance Analysis of Microarrays (SAM) and Linear Models for Microarray Data (LIMMA) revealed 112 significant differentially expressed genes (Figure 3A and Table S7). Some genes such as GPX3 and eEF1A2 have been reported being elevated in ovarian tumors including OCCC [16, 17]. Submission of the gene list for enrichment analysis using Ingenuity Pathway Analysis (IPA) platform demonstrated that most of these genes are involved in cell-to-cell signaling and cell morphology functions (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Four novel differentially expressed biomarkers were selected for further studies. eEF1A2 has been implicated as an oncogene in ovarian pathogenesis [16]; PTCH2 is involved in hedgehog signaling and it modulates tumorigenesis in the presence of Ptch1 haploinsufficiency in medulloblastoma and other tumors [22]; PPP1R14B is an inhibitor of protein-phosphatase 1 and is required for cell migration and retraction [23]; XRCC5 is one subunit of the Ku ATP-dependent DNA helicase heterodimer for double-strand break rejoining repair and was found upregulated in ovarian cancer triggered in response to genotoxic stress [24]. Besides overexpression of these four novel biomarkers in OCCC, IHC also showed that they were overexpressed in endometriosis associated with OCCC as compared to endometriosis in patients without cancer.…”

Section: Discussionmentioning

confidence: 99%

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Molecular changes in endometriosis-associated ovarian clear cell carcinoma

Worley

Liu

Hua

et al. 2015

European Journal of Cancer

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BACKGROUND Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood. METHODS We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin-embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments. RESULTS PTEN was significantly lost in both endometriosis and invasive tumor tissues, while estrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2, and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p≤0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodeling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker WT1 in OCCC, while endometriotic tissues showed significant co-expression of WT1 and ER. CONCLUSIONS Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic program for lineage-specific transformation of endometriosis to OCCC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

Worley

Liu

Hua

et al. 2015

European Journal of Cancer

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“…Although eEF1A2 was consistently overexpressed in all four I-144RZ and I-80RZ lines, the q20.13 locus where the EEF1A2 gene is located was amplified only in the I-80RZ lines but not in the I-144RZ lines (8). It has been reported previously that copy numbers of EEF1A2 do not always correlate with expression levels of the gene, indicating that eEF1A2 expression and/or protein levels must also be regulated at other levels (15). The fact that, in our studies, eEF1A2 was overexpressed in lines with and without 20q13 amplification indicates that, similar to Tomlinson’s observations (15, 16), mechanisms besides gene dosage were responsible for its overexpression.…”

Section: Discussionmentioning

confidence: 96%

“…There is increasing evidence that it also exerts oncogenic functions. eEF1A2 is amplified and overexpressed in ovarian cancers (14, 15), and is overexpressed in cancers of the breast and lung (16, 17, 18, 19). It also induces neoplastic properties in NIH3T3 cells (14).…”

Section: Introductionmentioning

confidence: 99%

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

Sun

Wong

Guan

et al. 2008

Intl Journal of Cancer

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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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“…The eEF1A family of peptide elongation factor comprises two isoforms, eEF1A1 and eEF1A2, encoded by different chromosomes but sharing 98% homology (7). Whereas the eEF1A1 is widely expressed in almost all tissues, the eEF1A2 is normally expressed in brain, heart, and skeletal muscle (7)(8)(9). Recent studies have revealed that members of eEF1A family play a critical role in carcinogenesis (10,11).…”

Section: Introductionmentioning

confidence: 99%

Resveratrol Suppresses Growth of Human Ovarian Cancer Cells in Culture and in a Murine Xenograft Model: Eukaryotic Elongation Factor 1A2 as a Potential Target

Lee¹,

Choi²,

Kundu³

et al. 2009

Cancer Research

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The eukaryotic elongation factor 1A2 (eEF1A2) is known to retain oncogenic potential and is recognized as a novel target for cancer prevention and therapy. Resveratrol (trans-3,4 ¶,5-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the growth-inhibitory effects of resveratrol in human ovarian cancer PA-1 cells, considering eEF1A2 as a potential molecular target. Pretreatment with resveratrol attenuated proliferation of serum-starved PA-1 cells stimulated with insulin or serum. Resveratrol also activated caspase-9, -7, and -3 and induced apoptosis in PA-1 cells in the presence of insulin or serum. Insulin or serum stimulation of PA-1 cells resulted in the marked induction of eEF1A2, which was suppressed by pretreatment with resveratrol. Moreover, resveratrol inhibited insulin-or serum-induced soft-agar colony formation in eEF1A2-transfected NIH3T3 cells. An antibody array directed to assess the phosphorylation of protein kinases revealed that treatment with insulin or serum induced the phosphorylation of Akt in PA-1 cells. Pharmacologic inhibition of Akt with LY294002 abrogated insulin-or serum-induced eEF1A2 expression and increased the caspase-3 activity. In another experiment, i.p. administration of resveratrol retarded the growth of PA-1 cell xenograft and the expression of eEF1A2 in athymic nude mice in association with decreased bromodeoxyuridine positivity, reduced expression of proliferating cell nuclear antigen, increased the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and caspase-3 staining, and diminished CD31 positivity. Taken together, eEF1A2 may be considered as a potential molecular target for the antiproliferative effects of resveratrol in PA-1 ovarian cancer cells.

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Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus

Cited by 40 publications

References 18 publications

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

Molecular changes in endometriosis-associated ovarian clear cell carcinoma

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

Resveratrol Suppresses Growth of Human Ovarian Cancer Cells in Culture and in a Murine Xenograft Model: Eukaryotic Elongation Factor 1A2 as a Potential Target

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