Expression of CPPED1 in human trophoblasts is associated with timing of term birth

Abstract

Understanding of timing of human parturition is incomplete. Therefore, we carried out proteomic analyses of full‐term placentas from uncomplicated pregnancies to identify protein signatures associated with the onset of spontaneous delivery. We found quantitative associations of 10 proteins with spontaneous term birth, evident either in the basal or in the chorionic plates or in both. Additional 18 proteins were associated according to the location within placenta indicating local variations in protein amounts. Calcineurin‐like phosphoesterase domain‐containing 1 (CPPED1), a phosphatase previously suggested dephosphorylating AKT1/PKB, was one of the identified proteins. qRT‐PCR revealed the mRNA level of CPPED1 was higher in elective caesarean deliveries than in spontaneous births, while immunohistochemistry showed CPPED1 in cytotrophoblasts, syncytiotrophoblasts and extravillous trophoblasts. Noteworthy, phosphorylation status of AKT1 did not differ between placentas from elective caesarean and spontaneous deliveries. Additionally, analyses of samples from infants indicated that single‐nucleotide polymorphisms rs11643593 and rs8048866 of CPPED1 were associated with duration of term pregnancy. Finally, post‐transcriptional silencing of CPPED1 in cultured HTR8/SVneo cells by siRNAs affected gene expression in pathways associated with inflammation and blood vessel development. We postulate that functions regulated by CPPED1 in trophoblasts at choriodecidual interphase have a role in the induction of term labour, but it may be independent of AKT1.

Spontaneous premature birth as a target of genomic research

“…A recent analysis investigated SNVs (n = 77) in ten fetal genes encoding placental proteins associated with the duration of pregnancy. Of these, only a SNV within CPPED1 associated with pregnancy duration (71). Both CPPED1 protein and CPPED1 mRNA in the basal plate of the placenta were associated with labor and length of pregnancy.…”

“…CPPED1 is a phosphatase that inactivates AKT1 in the PI3K/AKT1 signaling pathway in bladder cancer cells (72). A pathway analysis in which siRNA was used to inhibit CPPED1 expression in trophoblastderived cells revealed that CPPED1 affects expression of genes involved in angiogenesis and proximal PI3K/AKT1 signaling pathways (71). Potential phosphorylation targets of AKT1 include inactivation of hypo phosphorylated FOXO1, which participates in the progesterone receptor B (PR-B) transcriptional complex (73).…”

CPPED1-targeting microRNA-371a-5p expression in human placenta associates with spontaneous delivery

“…previously [23,39]. Briefly, qPCR was done as an intron-spanning assay with the LightCy-cler196 (Roche).…”

“…We showed previously that expression levels of calcineurin like phosphoesterase domain containing protein 1 (CPPED1) are associated with timing of birth and that spontaneous term placentas have decreased levels of CPPED1 compared to elective term placentas of deliveries without signs or symptoms of labor [23]. Additionally, expression of CPPED1 is decreased in invasive bladder cancer and overexpression of CPPED1 delays progression of the cell cycle [24].…”

“…We found variations in miRNA expression profiles during spontaneous term labor. By comparing the miRNAome data with our previously published human placental proteome [23], we identified a putative labor-associated miRNA:protein pair: miR-371a-5p:CPPED1. MiR-371a-5p is part of the pregnancy-specific miR-371-3 cluster.…”