Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets.
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Pamela L. Strissel1*, Matthias Ruebner1*, Falk Thiel1, David Wachter2, Arif B. Ekici3, Friedericke Wolf1, Franziska Thieme1, Klemens Ruprecht4, Matthias W. Beckmann1, Reiner Strick1
1 University-Clinic Erlangen, Department of Gynecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Germany
2 Institute of Pathology, Erlangen, Germany
3 Institute of Human Genetics, Erlangen, Germany;
4 Department of Neurology, Charité-University Medicine, Berlin, Germany
* denotes equal contribution
Reiner Strick, email:
Keywords: Endometrial carcinoma; hyperplasia; polyp; ERV; Syncytin
Received: September 27, 2012, Accepted: October 11, 2012, Published: October 13, 2012
Endometrial carcinoma (EnCa) is the most common invasive gynaecologic carcinoma. Over 85% of EnCa are classified as endometrioid, expressing steroid hormone receptors and mostly involving pathological prestages. Human endogenous retroviruses (ERV) are chromosomally integrated genes, account for about 8% of the human genome and are implicated in the etiology of carcinomas. The majority of ERV envelope (env) coding genes are either not present or not consistently represented between common gene expression microarrays. The aim of this study was to analyse the absolute gene expression of all known 21 ERV env genes including 19 codogenic and two env genes with premature stop codons in EnCa, endometrium as well as in hyperplasia and polyps. For EnCa seven env genes had high expression with >200 mol/ng cDNA (e.g. envH1-3, Syncytin-1, envT), two middle >50 mol/ng cDNA (envFc2, erv-3) and 12 low <50 mol/ng cDNA (e.g. Syncytin-2, envV2). Regarding tumor parameters, Syncytin-1 and Syncytin-2 were significantly over-expressed in advanced stage pT2 compared to pT1b. In less differentiated EnCa Syncytin-1, erv-3, envT and envFc2 were significantly over-expressed. Syncytin-1, Syncytin-2 and erv-3 were specific to glandular epithelial cells of polyps, hyperplasia and EnCa using immunohistochemistry. An analysis of 10 patient-matched EnCa with endometrium revealed that the ERV-W 5’ long terminal repeat regulating Syncytin-1 was hypomethylated, including the ERE and CRE overlapping MeCP2 sites. Functional analyses showed that 10 env genes were regulated by methylation in EnCa using the RL95-2 cell line. In conclusion, over-expressed env genes could serve as indicators for pathological pre-stages and EnCa.
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