Transcriptomic Analysis of Hub Genes Reveals Associated Inflammatory Pathways in Estrogen-Dependent Gynecological Diseases

Abstract

Simple Summary Gynecological diseases still make up a large percentage of the overall global disease burden. While oral contraceptives and gonadotropin-releasing hormone drugs for endometriosis and gynecological cancers exist, their known inflammatory side effects can counteract progress in therapy. With this, the present study made use of a systems biology approach to identify correlations between gynecological diseases using gene expression data from DNA microarray samples that contain endometriosis, ovarian cancer, cervical cancer, and endometrial cancer. The highly preserved gene modules and their top interacting hub genes were determined to provide a further understanding of the signaling pathways and biological processes affected. Potential drugs were screened based on the upregulated and downregulated hub genes, which identified drug candidates that have known anti-inflammatory effects, implying the potential of specific inflammatory pathways in estrogen-dependent gynecological diseases as a therapeutic avenue.Abstract Gynecological diseases are triggered by aberrant molecular pathways that alter gene expression, hormonal balance, and cellular signaling pathways, which may lead to long-term physiological consequences. This study was able to identify highly preserved modules and key hub genes that are mainly associated with gynecological diseases, represented by endometriosis (EM), ovarian cancer (OC), cervical cancer (CC), and endometrial cancer (EC), through the weighted gene co-expression network analysis (WGCNA) of microarray datasets sourced from the Gene Expression Omnibus (GEO) database. Five highly preserved modules were observed across the EM (GSE51981), OC (GSE63885), CC (GSE63514), and EC (GSE17025) datasets. The functional annotation and pathway enrichment analysis revealed that the highly preserved modules were heavily involved in several inflammatory pathways that are associated with transcription dysregulation, such as NF-kB signaling, JAK-STAT signaling, MAPK-ERK signaling, and mTOR signaling pathways. Furthermore, the results also include pathways that are relevant in gynecological disease prognosis through viral infections. Mutations in the ESR1 gene that encodes for ER alpha, which were shown to also affect signaling pathways involved in inflammation, further indicate its importance in gynecological disease prognosis. Potential drugs were screened through the Drug Repurposing Encyclopedia (DRE) based on the up-and downregulated hub genes, wherein a bacterial ribosomal subunit inhibitor and a benzodiazepine receptor agonist were the top candidates. Other drug candidates include a dihydrofolate reductase inhibitor, glucocorticoid receptor agonists, cholinergic receptor agonists, selective serotonin reuptake inhibitors, sterol demethylase inhibitors, a bacterial antifolate, and serotonin receptor antagonist drugs which have known anti-inflammatory effects, demonstrating that the gene network highlights specific inflammatory pathways as a therapeutic avenue in designing drug candidates for gynecological diseases.