Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta.
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.
Strick
Reiner
R
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
Ackermann
Sven
S
Langbein
Manuela
M
Swiatek
Justine
J
Schubert
Steffen W
SW
Hashemolhosseini
Said
S
Koscheck
Thomas
T
Fasching
Peter A
PA
Schild
Ralf L
RL
Beckmann
Matthias W
MW
Strissel
Pamela L
PL
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
D015686:Gene Products, env; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C405335:syncytin