ORIGINAL ARTICLE: Supporting the Hypothesis of Pregnancy As a Tumor: Survivin Is Upregulated in Normal Pregnant Mice and Participates in Human Trophoblast Proliferation

Authors

  • Stefan Fest,

    1. Experimental Oncology, Department of Paediatrics, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Nadja Brachwitz,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Anne Schumacher,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Maria Laura Zenclussen,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Faisal Khan,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Paul O. Wafula,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Pablo A. Casalis,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Sara Fill,

    1. Reproductive Immunology Group, Experimental Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Medical Faculty, Otto-von- Guericke University, Magdeburg, Germany
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  • Serban-Dan Costa,

    1. Reproductive Immunology Group, Experimental Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Medical Faculty, Otto-von- Guericke University, Magdeburg, Germany
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  • Gil Mor,

    1. Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, Yale University, New Haven, CT, USA
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  • Hans-Dieter Volk,

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Holger N. Lode,

    1. Experimental Oncology, Department of Paediatrics, Charité Universitätsmedizin Berlin, Berlin, Germany
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  • Ana Claudia Zenclussen

    1. Reproductive Immunology Group, Institute of Medical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
    2. Reproductive Immunology Group, Experimental Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Medical Faculty, Otto-von- Guericke University, Magdeburg, Germany
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Ana Claudia Zenclussen, Reproductive Immunology Group, Experimental Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Medical Faculty, Otto-von-Guericke University, Gerhart-Hauptmann Street 35, 39108 Magdeburg, Germany.
E-mail: ana.zenclussen@med.ovgu.de

Abstract

Problem  Survivin, a tumor-promoting antiapoptotic molecule, is expressed in the human placenta. Here, we analyzed its expression during normal and pathological murine pregnancy and investigated its participation in human first trimester trophoblast cell survival and proliferation.

Method of study  We first analyzed the expression of survivin on the mRNA and protein level at the fetal–maternal interface of normal pregnant (CBA/J × BALB/c) and abortion-prone (CBA/J × DBA/2J) mice at different pregnancy stages by RT-PCR and immunohistochemistry. We also evaluated apoptosis in murine trophoblasts in both mating combinations by TUNEL technique. Functional studies were carried out by knockdown survivin by means of siRNA methodology in two human first trimester trophoblast cell lines [Swan.71 (Sw.71) and HTR8 (H8)].

Results  We observed a peak in mRNA levels on day 5 and a peak of protein levels on day 8 of pregnancy in both combinations. The level of survivin in animals from the abortion-prone group was decreased compared with normal pregnant mice on day 8, which was accompanied by elevated apoptosis rates. In later pregnancy stages (days 10 and 14), survivin levels decreased to levels comparable to those observed right after fecundation in both groups. Transfection of human first trimester cell lines (H8 and Sw.71) with siRNA targeting the survivin gene led to a 76–82% reduction of its expression leading to reduced trophoblast cell viability and proliferation.

Conclusion  Our findings suggest an important role of survivin to promote trophoblast cell survival and proliferation during placentation, thus maintaining pregnancy. The pregnancy-associated expression of a cancer molecule such as survivin supports the ‘pseudo-malignancy’ hypothesis of pregnancy. Our data may contribute to the better understanding of trophoblast cell development during implantation and placentation.

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