Identification of key genes in the pathogenesis of preeclampsia via bioinformatic analysis and experimental verification

Background Preeclampsia (PE) is the primary cause of perinatal maternal-fetal mortality and morbidity. The exact molecular mechanisms of PE pathogenesis are largely unknown. This study aims to identify the hub genes in PE and explore their potential molecular regulatory network. Methods We downloaded the GSE148241, GSE190971, GSE74341, and GSE114691 datasets for the placenta and performed a differential expression analysis to identify hub genes. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), Gene Set Enrichment Analysis (GSEA), and Protein–Protein Interaction (PPI) Analysis to determine functional roles and regulatory networks of differentially expressed genes (DEGs). We then verified the DEGs at transcriptional and translational levels by analyzing the GSE44711 and GSE177049 datasets and our clinical samples, respectively. Results We identified 60 DEGs in the discovery phase, consisting of 7 downregulated genes and 53 upregulated genes. We then identified seven hub genes using Cytoscape software. In the verification phase, 4 and 3 of the seven genes exhibited the same variation patterns at the transcriptional level in the GSE44711 and GSE177049 datasets, respectively. Validation of our clinical samples showed that CADM3 has the best discriminative performance for predicting PE Conclusion These findings may enhance the understanding of PE and provide new insight into identifying potential therapeutic targets for PE.

[1]  Ž. Bojić-Trbojević,et al.  IL-6 and IL-8: An Overview of Their Roles in Healthy and Pathological Pregnancies , 2022, International journal of molecular sciences.

[2]  M. Padula,et al.  Maternal plasma proteome profiling of biomarkers and pathogenic mechanisms of early-onset and late-onset preeclampsia , 2022, Scientific Reports.

[3]  Tonglian Wang,et al.  Sangerbox: A comprehensive, interaction‐friendly clinical bioinformatics analysis platform , 2022, iMeta.

[4]  Danfeng Yu,et al.  Prediction of Differentially Expressed Genes and a Diagnostic Signature of Preeclampsia via Integrated Bioinformatics Analysis , 2022, Disease markers.

[5]  Jinzhu Jia,et al.  Development and Validation of Multi-Stage Prediction Models for Pre-eclampsia: A Retrospective Cohort Study on Chinese Women , 2022, Frontiers in Public Health.

[6]  Lei Lei,et al.  Integrated Analysis Identifies Four Genes as Novel Diagnostic Biomarkers Which Correlate with Immune Infiltration in Preeclampsia , 2022, Journal of immunology research.

[7]  Jing Zhang,et al.  IL-1β-induced pentraxin 3 inhibits the proliferation, invasion and cell cycle of trophoblasts in preeclampsia and is suppressed by IL-1β antagonists , 2022, Molecular Medicine Reports.

[8]  Jiha Shin,et al.  Targeting TBK1 Attenuates LPS-Induced NLRP3 Inflammasome Activation by Regulating of mTORC1 Pathways in Trophoblasts , 2021, Frontiers in Immunology.

[9]  Zhonglu Ren,et al.  Distinct placental molecular processes associated with early-onset and late-onset preeclampsia , 2021, Theranostics.

[10]  T. Rosen,et al.  miR-15b-5p promotes expression of proinflammatory cytokines in human placenta by inhibiting Apelin signaling pathway. , 2020, Placenta.

[11]  Liping Huang,et al.  Expression of SASH1 in Preeclampsia and Its Effects on Human Trophoblast , 2020, BioMed research international.

[12]  S. Oparil,et al.  Preeclampsia-Pathophysiology and Clinical Presentations: JACC State-of-the-Art Review. , 2020, Journal of the American College of Cardiology.

[13]  Zhonglu Ren,et al.  Landscape of Dysregulated Placental RNA Editing Associated With Preeclampsia , 2020, Hypertension.

[14]  James H. Joly,et al.  Differential Gene Set Enrichment Analysis: A statistical approach to quantify the relative enrichment of two gene sets , 2019, bioRxiv.

[15]  K. Conrad,et al.  Evidence for shared molecular pathways of dysregulated decidualization in preeclampsia and endometrial disorders revealed by microarray data integration , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  Jinhua Wu,et al.  Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis of placental microvascular endothelial cells during severe pre-eclampsia pathogenesis. , 2019, Placenta.

[17]  B. Sunguya,et al.  Postpartum depression among women with pre-eclampsia and eclampsia in Tanzania; a call for integrative intervention , 2019, BMC Pregnancy and Childbirth.

[18]  G. Gloor,et al.  Placental microRNAs in pregnancies with early onset intrauterine growth restriction and preeclampsia: potential impact on gene expression and pathophysiology , 2019, BMC Medical Genomics.

[19]  N. Shan,et al.  Development of Postpartum Depression in Pregnant Women with Preeclampsia: A Retrospective Study , 2019, BioMed research international.

[20]  Michelle Giglio,et al.  Human Disease Ontology 2018 update: classification, content and workflow expansion , 2018, Nucleic Acids Res..

[21]  M. Post,et al.  The von Hippel Lindau tumour suppressor gene is a novel target of E2F4-mediated transcriptional repression in preeclampsia. , 2018, Biochimica et biophysica acta. Molecular basis of disease.

[22]  V. Sandrim,et al.  Circulating Heme Oxygenase-1: Not a Predictor of Preeclampsia but Highly Expressed in Pregnant Women Who Subsequently Develop Severe Preeclampsia , 2018, Oxidative medicine and cellular longevity.

[23]  Yan Wang,et al.  Comparative gene expression profile and DNA methylation status in diabetic patients of Kazak and Han people , 2018, Medicine.

[24]  S. Drăghici,et al.  Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia , 2018, Front. Immunol..

[25]  Yangyu Zhao,et al.  miR-518b Enhances Human Trophoblast Cell Proliferation Through Targeting Rap1b and Activating Ras-MAPK Signal , 2018, Front. Endocrinol..

[26]  Hongmei Lin,et al.  Identification of potential crucial genes associated with early‐onset pre‐eclampsia via a microarray analysis , 2017, The journal of obstetrics and gynaecology research.

[27]  A. Krieg,et al.  HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia , 2016, Proceedings of the National Academy of Sciences.

[28]  S. Hansson,et al.  Inflammatory processes are specifically enhanced in endothelial cells by placental-derived TNF-α: Implications in preeclampsia (PE). , 2016, Placenta.

[29]  Wei-ping Zhou,et al.  Gene expression profiling reveals different molecular patterns in G-protein coupled receptor signaling pathways between early- and late-onset preeclampsia. , 2016, Placenta.

[30]  J. Tanus-Santos,et al.  Plasma from pre‐eclamptic patients induces the expression of the anti‐angiogenic miR‐195‐5p in endothelial cells , 2016, Journal of cellular and molecular medicine.

[31]  R. Fry,et al.  Epigenetics and Preeclampsia: Defining Functional Epimutations in the Preeclamptic Placenta Related to the TGF-β Pathway , 2015, PloS one.

[32]  D. Bartel,et al.  Predicting effective microRNA target sites in mammalian mRNAs , 2015, eLife.

[33]  Y. Li,et al.  Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction. , 2015, The Journal of clinical endocrinology and metabolism.

[34]  R. An,et al.  Identification of Early-Onset Preeclampsia-Related Genes and MicroRNAs by Bioinformatics Approaches , 2015, Reproductive Sciences.

[35]  Y. Okuno,et al.  Reliable pre-eclampsia pathways based on multiple independent microarray data sets. , 2015, Molecular human reproduction.

[36]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[37]  Chung-Yen Lin,et al.  cytoHubba: identifying hub objects and sub-networks from complex interactome , 2014, BMC Systems Biology.

[38]  Juancarlos Chan,et al.  Gene Ontology Consortium: going forward , 2014, Nucleic Acids Res..

[39]  J. Parker,et al.  Bioinformatic Approach to the Genetics of Preeclampsia , 2014, Obstetrics and gynecology.

[40]  Hui Zhou,et al.  starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data , 2013, Nucleic Acids Res..

[41]  M. Lappas,et al.  Apelin Is Decreased With Human Preterm and Term Labor and Regulates Prolabor Mediators in Human Primary Amnion Cells , 2013, Reproductive Sciences.

[42]  Damian Szklarczyk,et al.  STRING v9.1: protein-protein interaction networks, with increased coverage and integration , 2012, Nucleic Acids Res..

[43]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[44]  K. Osungbade,et al.  Public Health Perspectives of Preeclampsia in Developing Countries: Implication for Health System Strengthening , 2011, Journal of pregnancy.

[45]  I. Kovalszky,et al.  Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar. , 2011, Placenta.

[46]  Tiao-Lai Huang,et al.  Higher serum tropomyosin-related kinase B protein level in major depression , 2010, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[47]  Junli Zhao,et al.  Differential expression of microRNAs in the placentae of Chinese patients with severe pre-eclampsia , 2009, Clinical chemistry and laboratory medicine.

[48]  K. Münstedt,et al.  The gonadotropins: Tissue-specific angiogenic factors? , 2007, Molecular and Cellular Endocrinology.

[49]  H. Seppo,et al.  Tumor suppressor and growth regulatory genes are overexpressed in severe early‐onset preeclampsia – an array study on case‐specific human preeclamptic placental tissue , 2005 .

[50]  G. Dekker,et al.  Pre-eclampsia , 2005, The Lancet.

[51]  T. Libermann,et al.  Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia , 2003 .

[52]  Gary D Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[53]  S. Lenzen,et al.  2-oxocarboxylic acids and function of pancreatic islets in obese-hyperglycaemic mice. Insulin secretion in relation to 45Ca uptake and metabolism. , 1980, The Biochemical journal.

[54]  OUP accepted manuscript , 2021, Nucleic Acids Research.

[55]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..