Increased Krüppel-like factor 12 impairs embryo attachment via downregulation of leukemia inhibitory factor in women with recurrent implantation failure

摘要

Recurrent implantation failure (RIF) caused by various etiological factors remains a challenge for fertility clinicians using assisted reproductive technology (ART) worldwide. Dysregulation of leukemia inhibitory factor (LIF) in the endometria of women with RIF is involved in impaired endometrial receptivity and embryo adhesion. However, the mechanism through which LIF expression is regulated in women with RIF is still poorly understood. Our previous study noted that the abnormally increased endometrial Krüppel-like factor 12 (KLF12) in RIF women led to impaired decidualization and embryo implantation. Here, we further found that KLF12 inhibited embryo adhesion in vivo and in vitro by repressing LIF expression. Mechanistically, KLF12 bound to conserved sites (CAGTGGG, ?6771 to ?6765 and ?7115 to ?7109) within the LIF promoter region and repressed LIF transcription directly. Exogenous LIF significantly reversed the KLF12-mediated repression of BeWo spheroid adhesion. KLF12 expression was reduced significantly in Ishikawa cells treated with progestogen, which was due to the activation of Akt signaling. These findings may provide novel potential therapeutic regimens for patients with RIF and disrupted endometrial receptivity.