Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction

Nishizawa, Haruki; Ota, Sayuri; Suzuki, Manami; Kato, Takema; Sekiya, Takao; Kurahashi, Hiroki; Udagawa, Yasuhiro

doi:10.1186/1477-7827-9-107

Cited by 125 publications

(104 citation statements)

References 58 publications

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“…20 It has been reported that proliferation and apoptosis of trophoblasts are deregulated in preeclamptic placentas. [42][43][44] Interestingly, an increase in the mRNA of BCL6 in preeclamptic placentas has been observed independently by several groups, [21][22][23]26 yet its roles in the development of preeclampsia remain to be clarified. Recently, we have shown that BCL6 is indeed altered in preeclmaptic placentas, not only at its mRNA but also at its protein level.…”

Section: Discussionmentioning

confidence: 99%

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B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

et al. 2016

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Preeclampsia is one of the leading causes of maternal and perinatal mortality and morbidity and its pathogenesis is not fully understood. B-cell lymphoma 6 (BCL6), a key regulator of B-lymphocyte development, is altered in preeclamptic placentas. We show here that BCL6 is present in all 3 studied trophoblast cell lines and it is predominantly expressed in trophoblastic HTR-8/SVneo cells derived from a 1 st trimester placenta, suggestive of its involvement in trophoblast expansion in the early stage of placental development. BCL6 is strongly stabilized upon stress stimulation. Inhibition of BCL6, by administrating either small interfering RNA or a specific small molecule inhibitor 79-6, reduces proliferation and induces apoptosis in trophoblastic cells. Intriguingly, depletion of BCL6 in HTR-8/SVneo cells results in a mitotic arrest associated with mitotic defects in centrosome integrity, indicative of its involvement in mitotic progression. Thus, like in haematopoietic cells and breast cancer cells, BCL6 promotes proliferation and facilitates survival of trophoblasts under stress situation. Further studies are required to decipher its molecular roles in differentiation, migration and the fusion process of trophoblasts. Whether increased BCL6 observed in preeclamptic placentas is one of the causes or the consequences of preeclampsia warrants further investigations in vivo and in vitro.

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Section: Discussionmentioning

confidence: 99%

“…[21][22][23][24][25][26] Its involvement in the pathogenesis remains to be defined. We have recently shown that BCL6 is increased in both mRNA and protein level in preeclamptic placentas.…”

Section: Introductionmentioning

confidence: 99%

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

et al. 2016

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“…From the Research Centre for Women's and Infants' Health BioBank, we collected 157 placenta samples (BioBank samples) with detailed clinical data from a range of hypertensive and normotensive states. To increase our sample size, the BioBank samples were then combined with the 7 previously published placental microarray data sets 4,5,[28][29][30][31][32] (Table S1 in the online-only Data Supplement) that we have previously analyzed in aggregate (Aggregate samples). 13 The final combined data set contained 330 placentas (157 PE and 173 non-PE) and expression values for 14 651 genes found in common across all original microarray platforms.…”

Section: Assembly Of the Combined Data Setmentioning

confidence: 99%

“…As a first step toward class discovery of PE pathology, we performed an aggregated analysis of 7 previously published human PE placental microarray data sets 4,5,[28][29][30][31][32] using unbiased/ unsupervised multivariate clustering techniques. 13 Our methods, which improve on similar approaches used for the molecular subclassification of tumors in the oncology field, 33,34 blindly group samples based solely on similarities in gene expression, independent of clinical characteristics.…”

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confidence: 99%

Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia

et al. 2016

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P reeclampsia (PE) is a potentially life-threatening, systemic, hypertensive disorder affecting 3% to 5% of all pregnancies. Responsible for >60 000 maternal deaths each year, 1 PE is also a leading cause of fetal/neonatal mortality and morbidity. Classically, PE has been defined as new-onset hypertension and proteinuria after 20 weeks of gestation. However, the clinical presentation of PE is highly variable among women, and diagnostic guidelines now include signs and symptoms that are reflective of disease in ≥1 organ systems (liver, kidney, blood, and brain 2,3 ). Apart from expectant management and delivery of the infant and the placenta, there currently exists no cure or effective treatments for PE.The placenta is widely considered to be the central component of the PE disease process, and as it is not required after birth, this presents a unique opportunity to assess a clinically relevant tissue involved in a hypertensive pathology. Accordingly, numerous placental analyses have been conducted with the aim of identifying early detection markers or candidates for therapeutic intervention in PE. These studies have uncovered involvement of molecular pathways, such as oxidative stress and secretion, [4][5][6] and many secreted factors with disrupted expression during PE have been investigated as candidate blood biomarkers of this pathology. [7][8][9][10] However, the predictive power of these molecules demonstrate low sensitivity at clinically relevant false-positive rates 7 and, therefore, are not presently recommended for use as screening tools for PE. 11 We, [12][13][14] and others, 15,16 have proposed that this lack of robust biomarkers and effective treatments for PE is because of the multifactorial nature of this disease, a notion supported by considerable evidence within the human literature. [17][18][19][20][21] Further support also exists in the numerous developed animal models of PE that recapitulate many of the human symptoms and pathologies because these are the result of a range of initial insults, involving disruptions in placental 22,23 or maternal 24 genes, or a predisposing baseline maternal hypertension. 25 As such, past placental microarray, and even meta-analysis, 26,27 studies with small and highly selected patient cohorts, predominately assessed using a binary classification system (of PE versus control), do not accurately reflect the true clinical presentation of patients. Even the separation of women into earlyonset (diagnosis before 34 weeks) and late-onset PE groups 18,21 Abstract-Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervise...

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“…The mechanism of oxidative stress-mediated FGR is yet to be elucidated; it is generally believed that increased level of ROS induces a series of signal transduction mechanisms that eventually leads to apoptosis and various pathophysiological changes in the placenta leading to FGR [25].…”

Section: Discussionmentioning

confidence: 99%

Idiopathic Fetal Growth Restriction: Repercussion of Modulation in Oxidative Stress

et al. 2015

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Oxidative stress has been proposed as one of the causes involved in idiopathic fetal growth restriction (IFGR). However, the exact relationship between oxidative stress and IFGR is not understood. This study aimed at understanding the role of oxidative stress and antioxidant status in IFGR materno-fetal dyads and matched controls. 75 materno-fetal dyads with IFGR were enrolled with equal number of normal low risk controls. Malondialdehyde (MDA) levels were measured as marker of oxidative stress, while paraoxonase-1 (PON1) activity and total antioxidant capacity (TAC) of serum were measured as markers of antioxidant status. MDA levels were increased in both maternal and cord blood of IFGR neonates as compared to controls (p \ 0.001). TAC of serum were found to be decreased in IFGR (both maternal and cord blood) as compared to controls (p \ 0.001; p \ 0.05, respectively). PON1 activity was found to be decreased in the IFGR mothers while it was found increased in IFGR cord blood (p \ 0.01; p \ 0.001)). IFGR is a state of increased oxidative stress. Decreased PON1 enzymatic activity in mothers is also associated with IFGR.

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Comparative gene expression profiling of placentas from patients with severe pre-eclampsia and unexplained fetal growth restriction

Cited by 125 publications

References 58 publications

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

B-cell lymphoma 6 promotes proliferation and survival of trophoblastic cells

Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia

Idiopathic Fetal Growth Restriction: Repercussion of Modulation in Oxidative Stress

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