Bone marrow stromal cell antigen 2(BST2) suppresses the migration and invasion of trophoblasts in preeclampsia by downregulating matrix metallopeptidase 2(MMP2)

Preeclampsia is a grievous pregnancy-related complication with an incidence of approximately 5∼7% in pregnant women. Placental abnormalities and decreased placental perfusion associated with impaired trophoblast invasion are early pathological findings of preeclampsia. BST2 is a multifunctional transmembrane protein that plays critical roles in physiological and pathological processes, but its impacts and mechanisms of action in preeclampsia are inadequately understood. The aim of this manuscript was to investigate the functional impacts of BST2 and MMP2 on the biological behavior of trophoblast cells in preeclampsia. The expression of these proteins and their genes was analyzed by qRT-PCR, western blotting and immunohistochemistry. The results showed that the expression of BST2 and MMP2 was significantly downregulated in preeclampsia. The migration and invasion capacities of HTR-8/SVneo and JAR cells with overexpression or knockdown of BST2 were detected by wound healing assay and Transwell assays. It was found that BST2 overexpression could up-regulate <i>MMP2</i> expression, and enhance the migration and invasion capacity of HTR-8/SVneo and JAR cells. BST2 knockdown could reverse these effects. MMP2 knockdown could downregulate the invasion capacity of HTR-8/SVneo cells, and MMP2 overexpression reversed these effects. Pearson correlation analysis demonstrated that the expression of MMP2 and BST2 were positively correlated. These results indicate that the downregulation of BST2 lowers MMP2 expression and restraint trophoblast functions, which probably explain its role in the pathogenesis of preeclampsia.

子痫前期（preeclampsia）是一类严重的妊娠相关并发症，在孕妇群体中的发病率约为5%~7%。因滋养细胞侵袭受损引发的胎盘异常与胎盘灌注减少，是子痫前期的早期病理特征。BST2是一种多功能跨膜蛋白，在生理及病理过程中发挥关键调控作用，但其在子痫前期中的具体作用与分子机制尚未被充分阐明。本研究旨在探究BST2与基质金属蛋白酶2（MMP2）对子痫前期滋养细胞生物学行为的影响。研究通过实时荧光定量聚合酶链反应（qRT-PCR）、蛋白质免疫印迹（Western Blot）及免疫组化（immunohistochemistry），对两种蛋白及其编码基因的表达水平进行了检测分析。结果显示，子痫前期样本中BST2与MMP2的表达水平均显著下调。本研究采用划痕实验与Transwell实验，检测了过表达或敲低BST2的HTR-8/SVneo及JAR细胞的迁移与侵袭能力。结果发现，过表达BST2可上调MMP2的表达水平，并增强HTR-8/SVneo及JAR细胞的迁移与侵袭能力；而敲低BST2则可逆转上述效应。敲低MMP2可降低HTR-8/SVneo细胞的侵袭能力，而过表达MMP2则可逆转这一现象。皮尔逊相关分析结果表明，MMP2与BST2的表达水平呈显著正相关。综上，BST2表达下调会降低MMP2的表达水平并抑制滋养细胞功能，这或可解释BST2在子痫前期发病机制中的作用。