Proliferation and cell–cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-β
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Endometrial carcinomas (EnCa) predominantly represent a steroid hormone-driven tumor initiated from prestages. The human endogenous retrovirus HERV-W envelope gene Syncytin-1 was significantly increased at the mRNA and protein levels in EnCa and prestages compared to controls. Steroid hormone treatment of primary EnCa cells and cell lines induced Syncytin-1 due to a new HERV-W estrogen response element and resulted in increased proliferation. Activation of the cAMP-pathway also resulted in Syncytin-1 upregulation, but in contrast to proliferation, classic cell–cell fusions similar to placental syncytiotrophoblasts occurred. Cell–cell fusions were also histologically identified in endometrioid EnCa tumors in vivo. Clonogenic soft agar experiments showed that Syncytin-1 is also involved in anchorage-independent colony growth as well as in colony fusions depending on steroid hormones or cAMP-activation. The posttranscriptional silencing of Syncytin-1 gene expression and a concomitant functional block of induced cell proliferation and cell–cell fusion with siRNAs proved the essential role of Syncytin-1 in these cellular processes. TGF-β1 and TGF-β3 were identified as main regulative factors, due to the finding that steroid hormone inducible TGF-β1 and TGF-β3 inhibited cell–cell fusion, whereas antibody-mediated TGF-β neutralization induced cell–cell fusions. These results showed that induced TGF-β could override Syncytin-1-mediated cell–cell fusions. Interactions between Syncytin-1 and TGF-β may contribute to the etiology of EnCa progression and also help to clarify the regulation of cell–cell fusions occurring in development and in other syncytial cell tumors.
KeywordsTumorigenesis HERV Endometrial carcinoma Cell fusion TGF-beta
The authors are especially grateful to the patients who participated in this study and to the Department of Gynaecology, Erlangen. The authors wish to thank Prof. Dr. Papadopoulos at the Institute for Pathology, University of Erlangen for the histology of the tissue samples, Prof. Dr. C-M Becker (Institute for Biochemistry, University of Erlangen) for the use of the isotope laboratory, Mrs. Wenzel (Institute for Biochemistry) for cloning and sequencing, Mrs. Staerker and Toborek for hCG determinations, and Mrs. Oeser and Stiegler (Department of Gynecology) for their expert technical assistance. This study was partially supported by a grant from the DFG (#555/2-1).