title: Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta.
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-beta1 and TGF-beta3 were identified as main regulative factors, due to the finding that steroid hormone inducible TGF-beta1 and TGF-beta3 inhibited cell-cell fusion, whereas antibody-mediated TGF-beta neutralization induced cell-cell fusions. These results showed that induced TGF-beta could override Syncytin-1-mediated cell-cell fusions. Interactions between Syncytin-1 and TGF-beta 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.
authors.affiliation: Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, University Clinic Erlangen, Universitaetsstr. 21-23, 91054, Erlangen, Germany. Reiner.Strick@gyn.imed.uni-erlangen.de
authors.forename: Reiner
authors.initials: R
authors.lastname: Strick
authors.forename: Sven
authors.initials: S
authors.lastname: Ackermann
authors.forename: Manuela
authors.initials: M
authors.lastname: Langbein
authors.forename: Justine
authors.initials: J
authors.lastname: Swiatek
authors.forename: Steffen W
authors.initials: SW
authors.lastname: Schubert
authors.forename: Said
authors.initials: S
authors.lastname: Hashemolhosseini
authors.forename: Thomas
authors.initials: T
authors.lastname: Koscheck
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.forename: Ralf L
authors.initials: RL
authors.lastname: Schild
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Strissel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D002459:Cell Fusion; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015686:Gene Products, env / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D015151:Immunoblotting; D008875:Middle Aged; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D015686:Gene Products, env; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C405335:syncytin