Biological and pathobiological processes of human endometrium: endometrial receptivity, glucose metabolism, and cell migration

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Dokumentart: PhDThesis
Date: 2023-05-17
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Brucker, Sara (Prof. Dr.)
Day of Oral Examination: 2023-05-02
DDC Classifikation: 610 - Medicine and health
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In adolescents and young adult women with endometrial cancer, maintaining fertility is a crucial aspect in preserving a high quality of life. This cumulative thesis summarizes three published studies on the biology of endometrial cancer and endometrial receptivity. A deeper understanding of both may facilitate the development of a fertility-sparing treatment of endometrial cancer. The first study (Alauddin et al., 2020b) describes how annexin A7 (ANXA7), a phospholipid binding protein, affects fertility and embryo implantation. In this study, we performed in silico analysis of transcriptome data, in vivo experiments on AnxA7−/− and WT (AnxA7+/+) mice as well as in vitro measurements using human endometrial stromal cells. As a result, endometrial tissue expressed ANXA7 that rose in a time-dependent manner following decidualization of human endometrial stromal cells (HESCs). Silencing of ANXA7 reduces expression of canonical decidual marker genes, while increasing cyclooxygenase 2 and prostaglandin E2 levels. Moreover, number of implantation sites and litter sizes significantly increased in mice with genetic knockout of AnxA7. Furthermore, the study of human endometrial biopsies revealed that ANXA7 mRNA and protein levels are lower in women with recurrent pregnancy loss (RPL) during the midluteal window of implantation compared to subfertile individuals. In summary, our data suggests critical roles of ANXA7 in the regulation of endometrial receptivity and implantation. The second study (Zeng et al., 2020) investigated whether the endometrial bleeding related factor LEFTY2 physiologically involved in closure of the implantation window during menstrual cycle, may regulate the glucose metabolism of endometrial adenocarcinoma. Beyond fuelling glycolysis, glucose is used for glycogen synthesis for long-term storage. Reportedly, cancer cells may utilise Na+ coupled glucose transporter-1 (SGLT1; SLC5A1) for cellular glucose uptake. Here, we analysed the effect of LEFTY2 on SGLT1 expression and activity, as well as on glycogen synthesis in endometrial Ishikawa and HEC1a adenocarcinoma cells. LEFTY2 increased transcript and protein abundances of SGLT1 and glycogen synthase-1 in both cell lines. In LEFTY2-stimulated Ishikawa but not in HEC1a cells, uptake of the glucose analogue 2-NBDG and cellular glycogen levels were significantly increased as compared to unstimulated cells. Co-treatment with TGF-β blunted these LEFTY2 effects, suggesting that LEFTY2 may upregulate glycogen synthesis in endometrial adenocarcinoma in a TGF-β dependent manner. Finally, the third published study to be included in this cumulative thesis (Alauddin et al., 2020a) analysed the possible effects of the ellagic acid metabolite Urolithin A on the progression of endometrial adenocarcinoma in vitro. To this end, the impact of Urolithin A on actin dynamics, proliferation and cell migration as well as the signalling underlying observed effects were determined. The data indicate that Urolithin A inhibited actin polymerization, cell proliferation and migration of endometrial adenocarcinoma cells likely by interfering with Rac1 and PAK1 expression and signalling suggesting a tumoristatic action of ellagic acid-rich diet.

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