Her specialization includes reproductive medicine and gynaecological endocrinology. Her research interests include the diagnosis and management of endometriosis and adenomyosis. She has published over 20 articles.

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Endometriosis (ENDO) is a common gynecological disease that causes infertility in many women. Previous studies noted that the dysregulation of Homeo box A10 (HOXA10) in the endometrium of women with ENDO was involved in the failure of embryo implantation. However, the mechanism by which HOXA10 expression is reduced in women with ENDO is still poorly understood. Here we found that a member of the calcium (Ca2+)-dependent cysteine protease family calpain7 (CAPN7), negatively correlated with HOXA10, was highly expressed in the endometrium of infertile women with ENDO and was significantly downregulated during the window of embryo implantation in mice. Overexpression of CAPN7 in Ishikawa cells or in the uterus of mice inhibited embryo implantation in vitro and in vivo. In the current study, we identified a sequence rich in proline, glutamic acid, serine, and threonine (PEST sequence) that enhanced the Ca2+-dependent degradation of HOXA10 by CAPN7. Furthermore, the interaction between HOXA10 and CAPN7 repressed the transcriptional activity and protein stability of HOXA10. In contrast, the administration of the calpain inhibitor ALLN reversed the CAPN7-induced HOXA10 degradation. Moreover, truncation of the PEST motif in HOXA10 abolished its CAPN7-dependent proteolysis. These studies reveal a novel pattern of HOXA10 regulation via PEST sequence-mediated calpain proteolysis that was demonstrated to be reversed by a calpain inhibitor. Thus, the inhibition of CAPN7-induced HOXA10 degradation may represent a novel potential therapeutic method to improve impaired embryo implantation in women with ENDO.

BackgroundA receptive endometrium is essential for maternal-embryonic molecular communication during implantation. However, the specific molecular regulatory mechanisms of the endometrial capacity remain poorly understood. Here, we examined activating transcription factor 3 (ATF3) expression in human endometria and the functional effect of ATF3 on embryo attachment in vitro.MethodsImmunohistochemistry (IHC) was used to assess the ATF3 expression patterns in human endometria. Quantitative real-time PCR (qRT-PCR), western blotting and immunofluorescence (IF) studies were applied to explore ATF3 expression in Ishikawa cells upon estrogen (E2) and medroxyprogesterone acetate (MPA) treatment. qRT-PCR and western blotting were performed to inspect LIF (leukemia inhibitory factor) expression after enhancement or inhibition of ATF3, and a luciferase reporter assay and ChIP-PCR were used to confirm the regulatory mechanism of ATF3 to LIF. Endometrial epithelial capacity was assessed by an in vitro model of attachment of BeWo spheroids to Ishikawa cells. Western blotting was performed to compare the expression of ATF3 in endometrial samples of recurrent implantation failure (RIF) patients with that in samples from fertile women (FER) who had undergone no less than one successful embryo transplantation.ResultsATF3 was located in human endometrial epithelial cells and stromal cells and was significantly induced by E2 and MPA in Ishikawa cells. Adenovirus-mediated overexpression of ATF3 in Ishikawa cells activated LIF promoter activity and enhanced its expression. Accordingly, the stimulation of BeWo spheroid adhesion promoted by ATF3 was inhibited by pretreatment with a specific antibody against LIF via the antibody-blocking assay. Moreover, ATF3 was aberrantly decreased in the endometria of RIF patients.ConclusionsOur findings suggest that ATF3 plays a significant role in regulating human endometrial receptivity and embryo attachment in vitro via up-regulation of leukemia inhibitory factor.Trial registrationConstruction and management of the Nanjing multi-center biobank. No. 2013-081-01. Registered 10 Dec. 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-017-0260-7) contains supplementary material, which is available to authorized users.

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