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

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.

Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses

“…Some cancers lose ERV DNA methylation and aberrantly overexpress ERVs Cohen et al, 1988;Larsen et al, 2009;Larsson et al, 2007;Rycaj et al, 2014;Strick et al, 2007;Strissel et al, 2012;Wang-Johanning et al, 2001;Wang-Johanning et al, 2007) while others maintain silencing. Aza can induce specific ERV transcripts in melanoma, choriocarcinoma, and endometrial cancer cells (Laska et al, 2013;Ruebner et al, 2013;Stengel et al, 2010) (Strissel et al, 2012).…”

Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

“…One of the endogenous fusogens that drives formation of the syncytiotrophoblast and is aberrantly expressed in human cancers is ERVWE1 (Mi et al 2000;Strick et al 2007). To investigate the cellular consequences of ERVWE1-induced cell fusion, we expressed ERVWE1 in normal and cancer cells.…”

“…ERVWE1 is one of the proteins that is expressed in cancer cells of multiple origins and mediates fusion of cells in human tumors (Larsson et al 2007;Strick et al 2007;Larsen et al 2009). Interestingly, both ERVWE1 and MV have been proposed as candidates for the local treatment of cancer via induction of cell fusion (Msaouel et al 2009;Lin et al 2010).…”

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

“…Assays were in duplicates (Strick et al, 2007). Cells were cotransfected with both siRNAs or with the pcNRSFwt or pcDNA3 control vectors 24 h before agarose set-up.…”