Lefty inhibits in vitro decidualization by regulating P57 and cyclin D1 expressions

Abstract

Endometrial decidualization is highly important for successful construction and maintenance of embryo implantation and pregnancy. Lefty gene at different menstrual cycle phases has different expressions, indicating its regulatory significance. To study the mechanism of Lefty in decidualization, human endometrial stromal cells (hESCs) were cultured and induced with medroxyprogesterone acetate (MPA) and 8-bromoadenosine-cAMP (8-Br-cAMP) in vitro as a research model. Our results showed that Lefty1 overexpression inhibited MPA- and 8-Br-cAMP-induced hESC decidualization and significantly reduced the secretion of prolactin (PRL) and insulin-like growth factor-binding protein 1 (IGFBP-1). With the inhibition of Lefty1 expression, hESC decidualization induced by MPA and 8-Br-cAMP became more remarkable, and the secretions of PRL and IGFBP-1 were higher too. Further tests indicated that during the process of decidualization, P57 expression increased, whereas cyclin D1 expression decreased. Although Lefty1 overexpression did not significantly change the expressions of P57 and cyclin D1, inhibition of Lefty1 expression resulted in more evident changes in P57 and cyclin D1 expressions. Meanwhile, cell cycle examination showed that Lefty1 overexpression reduced the cell cycle arrest at G1/S phase in the in vitro hESC decidualization model. Therefore, Lefty1 could regulate the cell cycle via modulating the expressions of P57 and cyclin D1 and then inhibit the decidualization in vitro.

Lefty-1 alleviates TGF-β1-induced fibroblast–myofibroblast transdifferentiation in NRK-49F cells

“… 30 , 31 Data also show that Lefty-1 may regulate the cell cycle by modulating the expressions of P57 and cyclin D1 to inhibit the decidualization process. 32 As observed in the present study, Lefty-1 regulates the cell cycle, which may be an important part of its suppression of the activation and proliferation of TGF-β1-induced NRK-49F cells. Overall, the results indicate that Lefty-1 is a crucial mediator of activation of Smad3, JNK-3 and BMP-5, all of which are critical signaling molecules for fibroblast–myofibroblast transdifferentiation in response to TGF-β1.…”

LEFTYA Activates the Epithelial Na+ Channel (ENaC) in Endometrial Cells via Serum and Glucocorticoid Inducible Kinase SGK1

“…Failure to down-regulate LEFTYA secretion during the mid-luteal phase of the cycle may lead to premature 'closure' of the uterine lumen via ENaC-mediated fluid absorption, resulting in implantation failure [20,39]. The present observations, however, do not provide insight into the purported inhibitory effects of LEFTYA on decidualization of the endometrial stroma [40,41]. A previous study reported that induction of ENaC activity in response to embryonic proteases promotes decidualization by depolarizing the cell membrane of epithelial cells, leading to activation of voltage gated Ca 2+ channels, induction of COX-2 in …”

TGFβ superfamily signaling and uterine decidualization

“…Consistent with the inhibitory role of LEFTY in uterine decidualization in mice, overexpression of LEFTY1 in human ESCs impairs their secretion of PRL and IGFBP1 [ 84 ]. Studies using human uterine fibroblast cells also support an inhibitory function of LEFTY in uterine decidualization, with the involvement of key transcription factors, FOXO1 and ETS proto-oncogene 1 (ETS1) [ 58 ].…”