title: Supporting the hypothesis of pregnancy as a tumor: survivin is upregulated in normal pregnant mice and participates in human trophoblast proliferation.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We first analyzed the expression of survivin on the mRNA and protein level at the fetal-maternal interface of normal pregnant (CBA/J x BALB/c) and abortion-prone (CBA/J x 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatrics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fest
authors.forename: Nadja
authors.initials: N
authors.lastname: Brachwitz
authors.forename: Anne
authors.initials: A
authors.lastname: Schumacher
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Zenclussen
authors.forename: Faisal
authors.initials: F
authors.lastname: Khan
authors.forename: Paul O
authors.initials: PO
authors.lastname: Wafula
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Casalis
authors.forename: Sara
authors.initials: S
authors.lastname: Fill
authors.forename: Serban-Dan
authors.initials: SD
authors.lastname: Costa
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Volk
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
authors.forename: Ana Claudia
authors.initials: AC
authors.lastname: Zenclussen
mesh_terms: D000022:Abortion, Spontaneous / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011256:Pregnancy Outcome; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins; D000077022:Survivin; D014327:Trophoblasts / Q000166:cytology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin