Endocrine Abstracts

Ovarian cancer (OC) seriously impacts on female health with high incidence and mortality, which is involved in a series of changes at the levels of genome, transcriptome, proteome, metabolome, and interactome. Among those multiomics, proteome and metabolome are the important elements of phenome. We carried out the phenome-centered multiomics in OCs for 3P medical approach, including quantitative proteomics (205 differentially expressed proteins, DEPs) between OC tissues and control ovaries, quantitative proteomics (1198 mtDEPs) and phosphoproteomics (58 phosphoproteins) of mitochondria isolated from OC and control ovarian tissues, quantitative proteomics (390 DEPs) in OC cell or animal model treated with and without ivermectin, and transcriptomics data (20115 genes) from 419 OC samples. Comprehensive analysis of these omics data found energy metabolism pathway was significantly changed: (i) the upregulations of rate-limiting enzymes PKM2 in glycolysis, IDH2 in Kreb’s cycle, and UQCRH in oxidative phosphorylation (OXPHOS) pathways, (ii) the upregulation of PDHB that converts pyruvate from glycolysis into acetyl-CoA in Kreb’s cycle, and (iii) the binding sites between miRNA (hsa-miR-186-5p) and RNA-binding protein (EIF4AIII) in those key proteins in energy metabolism pathways. Furthermore, lncRNA SNHG3 interacted with hsa-miR-186-5p and EIF4AIII. Ivermectin regulated the rate-limiting enzymes and other proteins in glycolysis, Kreb’s cycle, and OXPHOS pathways, and inhibited cell proliferation and promoted apoptosis of OC. Those results were further confirmed in the OC cell models, animal models, and clinical tissue samples, with energy metabolism and enzyme activity experiments. It clearly concluded that SNHG3 regulated energy metabolism through hsa-miR-186-5p and EIF4AIII to regulate the key proteins in the energy metabolism pathways; SNHG3 inhibitor can interfere with the energy metabolism to treat OCs; and ivermectin has new potential for OC treatment through regulating energy metabolism pathways. These findings provide more accurate understanding of molecular mechanisms of OCs and discovery of effective energy-metabolism-heterogeneity-based therapeutic drugs for OCs.