Potential role of Hematopoietic PBX-Interacting Protein (HPIP) in trophoblast fusion and invasion: Implications in pre-eclampsia pathogenesis.

Abstract

Pre-eclampsia is a known hypertensive disorder of pregnancy. While abnormal placentation and poor trophoblast invasion into maternal endometrium during blastocyst implantation are primary causes of pre-eclampsia, the underlying mechanisms remain elusive. Hematopoietic PBX-Interacting protein (HPIP) is an estrogen receptor (ER) interacting protein that plays a pivotal role in cell proliferation, migration, and differentiation; however, its role in trophoblast functions is largely unknown. In this study, we used BeWo cells as a model system to investigate trophoblast fusion and syncytialization, focusing on the role of HPIP in regulating these critical aspects of trophoblast functions. Herein, we report that HPIP expression declines during forskolin-induced trophoblast fusion in BeWo cells. In support of these observations, HPIP depletion enhanced forskolin-induced human chorionic gonadotropin-β (β-hCG), ERVWE1, and GCM1 expression, markers for trophoblast fusion. Furthermore, silencing of HPIP decreased cell invasion and epithelial to mesenchymal transition (EMT), a prerequisite for syncytialization in BeWo cells. Functional genomic studies further revealed a regulatory role for HPIP in a subset of gene networks involved in trophoblast fusion and EMT. We also uncovered that HPIP is a proteolytic substrate of furin, which is known to promote trophoblast cell fusion. Clinical data further indicated a significantly lower expression level of HPIP in pre-eclampsia subjects than in normal subjects. These findings imply that HPIP inhibits trophoblast fusion while promoting invasion and EMT, and its downregulation in trophoblasts might have implications for pre-eclampsia development.