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

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Endometrial carcinoma (EnCa) of endometrioid type mainly represents a steroid hormone driven tumor progression initiated from pre-stages. Due to the cell biological resemblance between the process of fetal blastocyst invasion and steroid hormone controlled growth into the maternal Endometrium and the development of tumor cells, we asked the question, if the human endogenous retrovirus (HERV)-W envelope gene, Syncytin, could be involved in the cell biology and tumorigenesis of endometrioid EnCa and its pre-clinical stages. Syncytin gene expression studies were performed using absolute and semi-quantitative real-time PCR, Northern and Western analysis. Syncytin steroid hormone growth studies and cell-cell fusion inductions as well as Syncytin-siRNA experiments involved culturing of EnCa primary cells and cell lines as well as FACS and microscopy analyses.TGF-β1 / β3 were determined using ELISA. Syncytin was found significantly increased at the mRNA and protein levels in EnCa and their pre-stages, as compared to patient matched control Endometrium. Steroid hormone treatment of EnCa induced Syncytin due to an estrogen receptor response element resulting in increased proliferation. Primary EnCa syncytial multinucleated cells were identified in stained paraffin sections. Activation of the cAMP signalling pathway resulted in Syncytin up-regulation, but induced EnCa cell-cell fusions similar to placental syncytiotrophoblasts. Steroid hormone induced cell proliferation and EnCa cell-cell fusions were blocked using Syncytin siRNA. In addition, steroid hormone inducible TGF-β1/ β3 abrogated cell-cell fusion leading to cell proliferation, whereas TGF-β1 / β3 neutralization induced cell-cell fusions, revealing TGF-β1 / β3 as a key regulators. An up-regulation of the endogenous retroviral gene Syncytin was identified in EnCa staging. The steroid hormone induction of Syncytin leading to increased cell proliferation contributes to the etiology of endometrioid EnCa tumor progression, which could also be essential for other steroid hormone driven tumors. Although Syncytin is a known placental bona fide gene involved in cell-cell fusions leading to syncytiotrophoblasts, Syncytin also mediates EnCa cell-cell fusions upon cAMP stimulation. Steroid hormone induced TGF-β1/β3 was identified as a dominant regulator promoting cell proliferation and inhibiting cell-cell fusion in EnCa. The identification of Syncytin as the key mediator of cell-cell fusions in EnCa tumor biology could help to unravel the functional role of cell fusions occurring in development and in other so called syncytial cell tumors.