Comprehensive analysis of placental gene-expression profiles and identification of EGFR-mediated autophagy and ferroptosis suppression in intrahepatic cholestasis of pregnancy

Abstract

Intrahepatic cholestasis of pregnancy (ICP) was the most common liver disease specific to pregnancy. The symptoms of ICP were maternal pruritus and increased bile acid level in serum which was related to preterm birth, fetal distress, meconium-stained amniotic fluid and stillbirth. However, the mechanism of ICP progression on fetal development remained obscure. Sequencing data of 2 normal placenta samples and 4 intrahepatic cholestasis samples during pregnancy was analyzed by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for analysis of differentially expressed genes. MCODE - A plug-in of Cytoscape was used for molecular complex detection. STRING, Cytoscape, GeneMANIA, NetworkAnalyst, TransmiR, JASPAR, DGIdb and DrugBank were used in this study. Furthermore, histopathological and cell experiments were used to verify our results. Our study identified the key KEGG pathway and four MCODEs which were closely with ICP development, further, sorted by degree centrality, we showed top 30 genes from 7209 differential genes, such as TP53, SRC, EGFR, ESR1, IL10, CD8A, MAPK3, PTPRC, EGF, KIT, ITGAM, LEP and CSF2, etc. Moreover, these hub genes participated in JAK-STAT3 signaling pathway and STAT1/3 regulated these genes expression in a direct way or miRNA-mediated manner. Drug-target analysis about up-regulated genes among hub genes showed that these genes contained multiple drug action site. Furthermore, hub gene-EGFR was associated with destroyed autophagy and ferroptosis. In conclusion, our study analyzed key genes and pathways in ICP development. JAK-STAT3 pathway and EGFR might be a potential target for ICP therapy.