Journal of Molecular Medicine

, Volume 85, Issue 1, pp 23–38 | Cite as

Proliferation and cell–cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-β

  • Reiner Strick
  • Sven Ackermann
  • Manuela Langbein
  • Justine Swiatek
  • Steffen W. Schubert
  • Said Hashemolhosseini
  • Thomas Koscheck
  • Peter A. Fasching
  • Ralf L. Schild
  • Matthias W. Beckmann
  • Pamela L. Strissel
Original Article

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.

Keywords

Tumorigenesis HERV Endometrial carcinoma Cell fusion TGF-beta 

Supplementary material

109_2006_104_MOESM1_ESM.doc (21 kb)
Supplemental Table 1(DOC 21 kb)
109_2006_104_MOESM2_ESM.doc (22 kb)
Supplemental Table 2(DOC 22 kb)
109_2006_104_Fig1_ESM.jpg (122 kb)
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)

109_2006_104_Fig2a-b_ESM.jpg (80 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)

109_2006_104_Fig3_ESM.jpg (207 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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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Reiner Strick
    • 1
  • Sven Ackermann
    • 1
  • Manuela Langbein
    • 1
  • Justine Swiatek
    • 1
  • Steffen W. Schubert
    • 2
  • Said Hashemolhosseini
    • 2
  • Thomas Koscheck
    • 3
  • Peter A. Fasching
    • 1
  • Ralf L. Schild
    • 1
  • Matthias W. Beckmann
    • 1
  • Pamela L. Strissel
    • 1
  1. 1.Department of Gynaecology and Obstetrics, Laboratory for Molecular MedicineUniversity Clinic ErlangenErlangenGermany
  2. 2.Institute for BiochemistryUniversity of Erlangen-NurembergErlangenGermany
  3. 3.Institute for PathologyUniversity of Erlangen-NurembergErlangenGermany

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