Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia

Abstract

We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach.

Plasma cancer biomarker multiplex screening and the risk of subsequent preeclampsia

“…The placenta abnormal implantation process is well known to play a major role in the development of disease [1]. The molecular mechanisms that are involved in normal placental implantation are tightly related to the proliferative and invasive capacity of trophoblast cells and recent evidence suggests a common convergence between PE genes and those involved in tumor progression [2][3][4]. Although the invasion process is increased in cancer and occurs to a lesser extent in PE, known cancer genes involved in tumor progression may be useful as potential PE biomarkers and could play a role in the PE etiopathogenesis.…”

An Integrative Analysis of Preeclampsia Based on the Construction of an Extended Composite Network Featuring Protein-Protein Physical Interactions and Transcriptional Relationships

“…Comparative studies suggest that the rank product method outperforms the other methods in terms of sensitivity and specificity, especially in a setting of small sample size and large between-study variation [34]. In addition to our studies, two other meta-analysis on transcriptomic datasets of preeclamptic placentas have been conducted recently [5, 6]. The study by Moslehi and coworkers was conducted on 4 datasets using a combining P-values method and identified a total of 419 DEGs.…”

“…To investigate the molecular mechanisms involved in this disease several studies have used genome-wide microarray expression analysis to identify differentially expressed Genes (DEGs) between the preeclamptic and the non-pathologic placenta; reviewed in [4]. Several DEGs have been found systematically modified in the preeclamptic placenta, including: LEP, FLT1, ENG, INHA [5–8]. Yet the characterization of the transcriptome signature of the preeclamptic placenta has not been followed by a detailed understanding on how the modifications in the expression of these genes impacts the function of the placenta.…”

Placental transcriptome in development and pathology: expression, function, and methods of analysis

“…Their analysis confirmed many past observations of hypoxia and blood vessel development as drivers of PE, but also identified altered carbohydrate metabolism and transcription. 92 These are interesting data, since it is well known that the maternal phenotype plays a strong role in the risk of developing PE. 94 However, while these individual and meta/aggregate microarray analyses have provided many credible insights into PE, the lack of an overall consensus between studies has resulted in limited clinical progress in terms of predicting and treating patients affected by this pathology.…”

“…79, 81 Vaiman et al 81 92 integrated multiple PE data sets into a larger data set. Their analysis confirmed many past observations of hypoxia and blood vessel development as drivers of PE, but also identified altered carbohydrate metabolism and transcription.…”