Aurora kinase mRNA expression is reduced with increasing gestational age and in severe early onset fetal growth restriction
Introduction
Preeclampsia is a life-threatening complication of pregnancy, characteristically causing hypertension and proteinuria, which can lead to multi-organ maternal injury in the kidneys, liver and brain, and in some cases, fetal growth restriction (FGR) [1]. Isolated FGR is caused by significant placental dysfunction leading to impaired intrauterine growth which, in severe cases, can lead to stillbirth [2]. Both placental disorders can necessitate pre-term delivery, that may lead to death or significant long-term disability in the neonate especially if they occur at extreme pre-term gestations [3].
Oxidative damage and biochemical ageing have been implicated as a cause of fetal death [4], and cellular senescence may play a role in the pathophysiology of preeclampsia, FGR and even spontaneous pre-term birth [5]. Cellular senescence can be induced by a variety of factors, such as oxidative stress, strong mitotic signals and dysregulation or activation of tumour suppressor genes [6]. Aurora kinases A (AURKA), B (AURKB) and C (AURKC) are members of a group of serine/threonine protein kinases with important regulatory roles in mitosis and meiosis, including M-phase entry, spindle formation and regulation, and cytokinesis [7]. AURKA is a major regulator of mitotic centrosomes and spindle assembly and is required for cell cycle progression [8]. AURKB expression is decreased in a p53-dependent manner in human primary cells (human dermal fibroblasts and human umbilical vein endothelial cells) undergoing senescence [7] and oocyte-specific Aurkb knockout female mice undergo premature age-related infertility [9]. Collectively, these data indicate an important role of AURKB in cellular ageing. Although AURKA and AURKB are found in all cell types throughout the body, significant levels of AURKC are found only in cells that undergo meiosis [10], with much lower expression in somatic cells such as the lung and placenta [11]. AURKC is also essential for healthy early pregnancy and knockout mice are subfertile with meiotic abnormalities and compromised embryonic development [12].
As well as a potential role in placental dysfunction, cellular senescence is also implicated in the pathophysiology of cancer [6]. Aurora kinases are overexpressed in highly invasive human tumours, leading to their consideration as a potential therapeutic target [[13], [14], [15], [16], [17]]. Activation of AURKB through the lysine methylation of Heat Shock Protein 70 (HSP70) may promote cancer cell proliferation [18]. HSP70 is also elevated in preeclampsia and is thought to originate from syncytiotrophoblasts and villous endothelial cells [19].
The link between cellular senescence and the aurora kinases, and the link between impaired early pregnancy development and AURKC, led us to first assess the possibility of a role by evaluating changes in the expression of aurora kinases in pregnancy in women. We aimed to investigate whether AURKA, AURKB and AURKC are altered with either disorders of placental dysfunction, or with placental ageing.
Section snippets
Study subjects
Placental tissue was obtained from women across gestations and were divided into early pre-term (<34 weeks; n = 17), late pre-term (34–37 weeks; n = 15), term (37–40 weeks; n = 21) and post-term (>40 weeks; n = 9). Control placental and blood samples were obtained from women who delivered at various gestations with an appropriately grown fetus. Pre-term control placentas were collected from women who spontaneously delivered a preterm baby, or were iatrogenically delivered for reasons such as
Placental expression of AURK across gestation
To determine whether the aurora kinases are altered in disorders of placental dysfunction, or with placental ageing, we first evaluated their mRNA expression levels by quantitative real-time PCR in placentas during the later stages of normal gestation. Using a ranked based test to examine placental expression in discrete gestational windows expression of both AURKA (p < 0.05) and AURKB (p < 0.01) mRNA was found to be significantly reduced at 37–40 weeks compared to earlier in gestation, at <34
Discussion
Placental ageing and cellular senescence are implicated in multiple aspects of placental dysfunction in pregnancy, including pre-term birth, fetal growth restriction, preeclampsia, and ultimately fetal death. The aurora kinases play an important role in cellular ageing and are known regulators of multiple cell-cycle stages. Because of this connection, we assessed aurora kinase mRNA levels in the placenta and maternal circulation, in both normal physiologically ageing placentas, and in the
Acknowledgements
We would like to thank the research midwives, Gabrielle Pell, Genevieve Christophers, Rachel Murdoch and Debra Jinks, obstetrics and midwifery staff, and patients at the Mercy Hospital for Women for provision placental tissue and blood samples. The NHMRC provided salary support (TKL; #1159261, ST; #1136418 and NJH; #1146128) and post-graduate scholarship support (NP; #1150828).
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