CircPAPPA binds to PAPPA and promotes trophoblast proliferation in spontaneous abortion through the formation of circPAPPA-PAPPA complexes

Abstract

Background

Spontaneous abortion (SA) is one of the most common complications of early pregnancy. Circular RNAs play an important regulatory role in the development of pregnancy-associated diseases in females. While PAPPA is known to be lower in several problematic pregnancy conditions, the specific role it plays in spontaneous abortion has not yet been clearly defined.

Methods

High-throughput sequencing and bioinformatics analysis were used to sort the circRNA expression profile in villus tissues from abortions that happened on their own. The presence and expression of circPAPPA in trophoblasts were detected by RNase-R digestion and RNA-FISH. The effect of circPAPPA on the proliferation of trophoblasts was evaluated by transfecting circRNA plasmids and siRNAs into the cells, followed by assessing the impact through the CCK-8 assay. Additionally, we investigated the localization and binding of circPAPPA and the PAPPA protein in trophoblasts through RNA FISH/IF, RIP and RNA pull-down assays.

Results

We identified and characterized a new circRNA, circPAPPA, whose expression is down-regulated in villus tissues from spontaneous abortion. And high levels of circPAPPA lead to increased trophoblast proliferation in vitro. CircPAPPA can bind to PAPPA protein; mechanistically, the binding of PAPPA protein to circPAPPA significantly influences how circPAPPA regulates trophoblast activity.

Conclusions

Altogether, our study shows that circPAPPA binds to PAPPA, enhancing trophoblast proliferation in vitro, and suggests that targeting the circPAPPA-PAPPA interaction might be a novel therapeutic strategy for addressing spontaneous abortion.