UBC Theses and Dissertations
Gonadotropin-releasing hormone (GnRH) regulates trophoblast invasion and vascular mimicry : involvement of cell-cell adhesion and proteolysis dynamics. Bo, Peng
To date, the pro-invasive role of the GnRH-GnRHR system has been demonstrated in several cell types including carcinoma cells. Placental expression of GnRH I, GnRH II, and their mutual receptor (GnRHR) is indicative of a potential mechanism(s) that occurs during the dynamic process of human placenta formation and differentiation, particularly during the development of an invasive phenotype of extravillous trophoblasts (EVTs). However, current studies haven’t completely revealed the role of GnRH in regulating invasive EVT function and the underlying mechanism(s) is not yet well-established. Dynamic reprogramming of cell adhesion and proteolytic machinery is frequently accompanied with cell invasive and angiogenic phenotypes. I hypothesized that GnRH could regulate trophoblast invasion and vascular remodeling via modulation of mesenchymal cadherins and matrix matelloproteinases (MMPs). In these studies, I have found that both GnRH forms could regulate N-cadherin and cadherin-11 expression distinctly by activating of transcription factors TWIST and c-FOS/c-JUN, respectively. Furthermore, I have demonstrated that GnRH I and GnRH II are capable of increasing MMP-2 and MMP-9 expression in EVT cells via up-regulation of the transcription factor RUNX2. Specific inhibition of TWIST/N-cadherin, c-FOS/c-JUN/cadherin-11 and RUNX2/MMP-2/MMP-9 in EVT cells attenuates both basal and GnRH-induced trophoblast invasion. Additionally, both forms of GnRH stimulate matrigel-mediated capillary-like network formation of trophoblastic cells and this phenomenon is also mediated by GnRH induced N-cadherin, cadherin-11, MMP-2 and MMP-9 expression. Collectively, our observations strengthen our hypothesis that GnRH is an important regulator of EVT cell behavior during implantation and placentation. These studies systemically described the underlying molecular mechanisms involved in GnRH induced adhesion molecule and proteolysis reprogramming.
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