YB-1 Is Altered in Pregnancy-Associated Disorders and Affects Trophoblast in Vitro Properties via Alternation of Multiple Molecular Traits.

Violeta Stojanovska,Aneri Shah,Peter R Mertens,Jonathan A Lindquist,Ana C Zenclussen,Mario Bauer,Florence Fischer,Katja Woidacki

doi:10.3390/ijms22137226

Abstract

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-B enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-B.

Highlights

Adequate placenta development is a prerequisite of a successful pregnancy, while inadequate placentation is a feature of many pregnancy-associated disorders, including spontaneous abortion, intrauterine growth restriction (IUGR), and preeclampsia (PE) [1,2]
To assess whether Y-box binding protein-1 (YB-1) is affected in early pregnancy events, we analyzed the YB-1 expression in placenta samples from spontaneous abortions and normally progressing pregnancies that were legally terminated, which served as controls
We checked the YBX1 levels in control term placentas and placentas obtained from late pregnancy events, such as preterm birth complicated by IUGR or PE syndrome

Summary

Introduction

Adequate placenta development is a prerequisite of a successful pregnancy, while inadequate placentation is a feature of many pregnancy-associated disorders, including spontaneous abortion, intrauterine growth restriction (IUGR), and preeclampsia (PE) [1,2] These disorders have complex pathophysiology with incompletely understood etiology, many share similar origins, such as inadequate trophoblast proliferation and shallow trophoblast invasion [3]. The placenta arises from the trophectoderm of the developing embryo, and, as soon as the embryo-derived trophoblasts adhere to the maternal endometrium, they start to proliferate, migrate towards the basal membrane, and invade into the surrounding endometrial stroma [4] They attain to remodel the spiral arteries under tightly balanced exposure to growth factors and cytokines derived from the surrounding immune and stromal cells [5]. Understanding of the molecular mechanisms underlying tumor growth and invasiveness might be of essential interest in understanding the trophoblast functionality, as well

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