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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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Abstract

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.

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Acknowledgments

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).

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Authors and Affiliations

  1. Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University Clinic Erlangen, Universitaetsstr. 21-23, 91054, Erlangen, Germany

    Reiner Strick, Sven Ackermann, Manuela Langbein, Justine Swiatek, Peter A. Fasching, Ralf L. Schild, Matthias W. Beckmann & Pamela L. Strissel

  2. Institute for Biochemistry, University of Erlangen-Nuremberg, 91054, Erlangen, Germany

    Steffen W. Schubert & Said Hashemolhosseini

  3. Institute for Pathology, University of Erlangen-Nuremberg, 91054, Erlangen, Germany

    Thomas Koscheck

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  1. Reiner Strick
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Correspondence to Reiner Strick.

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supplemental Fig. S1

Growth curves of BeWo, Kle, and RL95-2 cells in the presence of different steroid hormones, ddA or Forskolin. Open circle control, open triangle 10 nM E2, closed triangle 10 nM 4-OH-E2, closed square 1 μM estrone, cross 10 nM 2-OH-E2, closed circle 1 μM Estriol, closed diamond 10 mM ddA plus 10 nM E2, open square 500 nM progesterone, open diamond 40 μM Forskolin (JPEG 125 kb)

supplemental Fig. S2

a RT-PCR of Syncytin-1 (748 bp) and β-actin (382 bp) with RNA isolated from RL95-2 cells treated with 10 nM of either E2, 4OH-E2 (4E2), or 2OH-E2 (2E2), 1 μM estrone (E1), and 10 nM E2 plus 10 mM ddA. M DNA marker. b RT-PCR of Syncytin-1 (748 bp) and β-actin (382 bp) with RNA isolated from Syncytin-1 transfected RL95-2 cells at 4 days post transfection (c1). After 4 days post transfection the cells were cultivated for an additional 3 days (c), and treated with 10 nM E2 or 40 μM Forskolin (F) (JPEG 82 kb)

supplemental Fig. S3

Cultured BeWo cells were incubated with 10 nM E2 (E2), 40 μM SP-cAMP (SP-cAMP), 40 μM SP-cAMP plus 5 ng/ml TGF-β1 (SP-cAMP + TGF-β1), and 10 nM E2 plus 1 μg/ml anti-TGF-β1 (E2 + anti-TGF-β1), then stained with May–Grunwald and Giemsa (JPEG 211 kb)

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Strick, R., Ackermann, S., Langbein, M. et al. Proliferation and cell–cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-β. J Mol Med 85, 23–38 (2007). https://doi.org/10.1007/s00109-006-0104-y

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