BackgroundPelvic organ prolapse (POP) brings major health issues for women, affecting 40% of postmenopausal women, and directly affects bladder and bowel function, as well as quality of life. In light of the projected growth in demand for care for pelvic floor disorders, determining the etiology and progression of POP has important public health implications.Material/MethodsUterosacral ligaments (USLs) samples of POP patients and normal controls were enrolled for RNA-Seq, and functional annotation analysis and Protein-Protein interaction (PPI) networks construction were performed for differentially expressed genes (DEGs).ResultsA total of 81 DEGs were identified between POP and normal control, and distinctly classify all samples into normal and POP group by hierarchical clustering. Sixty-six DEGs demonstrated the same expression pattern among the POP samples with different stages. For those DEGs, canonical Wnt receptor signaling pathway was the most significantly enriched GO term (P value=3.33E-07), and neuroactive ligand-receptor interaction was the most significantly enriched pathway (P value=1.24E-03). In The PPI networks of 81 dysregulated genes, significant hub proteins contained TOP2A (Degree=54), KCNA5 (Degree=22) and PLA2G2A (Degree=19), suggesting their important role in the development of POP.ConclusionsThis RNA-seq analysis identified a POP signature of 81 genes, and some ECM-related genes, including COMP, NDP, and SNAI2 might participate in the pathology of POP and be applied as potential therapeutic targets.