伊藤 真友子

OBJECTIVES: Nectin-4 is a cell adhesion molecule with vital functions at adherens and tight junctions. Cumulative evidence now indicates that the NECTIN4 gene is overexpressed in a variety of cancers, and that the nectin-4 protein is both a disease marker and therapeutic target in a subset of these cancers. We previously demonstrated that NECTIN4 is overexpressed in placenta during pre-eclamptic pregnancy, which is one of the most serious obstetric disorders. METHODS: Nectin-4 protein levels were measured in maternal sera from pregnant women with pre-eclampsia and its related disorder, unexplained fetal growth retardation. RESULTS: Maternal serum concentrations of nectin-4 were significantly elevated in pre-eclamptic women compared with those with an uncomplicated normotensive pregnancy. However, no increase was observed in pregnancies with unexplained fetal growth retardation. Serum nectin-4 levels were higher in cases with early-onset pre-eclampsia that generally showed more severe clinical symptoms, but levels were not correlated to other clinical indicators of disease severity. CONCLUSIONS: Nectin-4 is a potential new diagnostic and predictive biomarker for severe pre-eclampsia.

BACKGROUND: FLT1 is one of the significantly overexpressed genes found in a pre-eclamptic placenta and is involved with the etiology of this disease. METHODS: We conducted genome-wide expression profiling by RNA-seq of placentas from women with pre-eclampsia and those with normotensive pregnancy. RESULTS: We identified a lncRNA gene, MG828507, located ~80 kb upstream of the FLT1 gene in a head-to-head orientation, which was overexpressed in the pre-eclamptic placenta. MG828507 and FLT1 are located within the same topologically associated domain in the genome. The MG828507 mRNA level correlated with that of the FLT1 in placentas from pre-eclamptic women as well as in samples from uncomplicated pregnancies. However, neither the overexpression nor knockdown of MG828507 affected the expression of FLT1. Analysis of pre-eclampsia-linking genetic variants at this locus suggested that the placental genotype of one variant was associated with the expression of MG828507. The MG828507 transcript level was not found to be associated with maternal blood pressure, but showed a relationship with birth and placental weights, suggesting that this lncRNA might be one of the pivotal placental factors in pre-eclampsia. CONCLUSION: Further characterization of the MG828507 gene may elucidate the etiological roles of the MG828507 and FLT1 genes in pre-eclampsia in a genomic context.

Atrial natriuretic peptide is biologically activated by the atrial natriuretic peptide-converting enzyme, corin, and has an important role in regulating blood pressure. We detected elevated serum corin levels in women with pre-eclampsia. Interestingly, the serum corin levels were also found to be elevated in pregnancies with a related disorder, unexplained fetal growth restriction (FGR) without hypertension, suggesting that this phenomenon is not simply a response to maternal hypertension. CORIN mRNA levels were not elevated in placentas from pre-eclampsia or unexplained FGR cases. Likewise, similar signal intensities were found for corin in placental syncytiotrophoblast cells by immunostaining. In contrast, corin signals were higher in maternal decidua cells from pre-eclampsia and unexplained FGR cases. These data suggest that corin may be upregulated in maternal decidua in response to an etiologic pathway that is common to pre-eclampsia and FGR. (C) 2016 Elsevier Ltd. All rights reserved.

Aneuploidy in fetal chromosomes is one of the causes of pregnancy loss and of congenital birth defects. It is known that the frequency of oocyte aneuploidy increases with the human maternal age. Recent data have highlighted the contribution of cohesin complexes in the correct segregation of meiotic chromosomes. In mammalian oocytes, cohesion is established during the fetal stages and meiosis-specific cohesin subunits are not replenished after birth, raising the possibility that the long meiotic arrest of oocytes facilitates a deterioration of cohesion that leads to age-related increases in aneuploidy. We here examined the cohesin levels in dictyate oocytes from different age groups of humans and mice by immunofluorescence analyses of ovarian sections. The meiosis-specific cohesin subunits, REC8 and SMC1B, were found to be decreased in women aged 40 and over compared with those aged around 20 years (P < 0.01). Age-related decreases in meiotic cohesins were also evident in mice. Interestingly, SMC1A, the mitotic counterpart of SMC1B, was substantially detectable in human oocytes, but little expressed in mice. Further, the amount of mitotic cohesins of mice slightly increased with age. These results suggest that, mitotic and meiotic cohesins may operate in a coordinated way to maintain cohesions over a sustained period in humans and that age-related decreases in meiotic cohesin subunits impair sister chromatid cohesion leading to increased segregation errors.