Big data analysis reveals miR-874 as a suppressor and therapeutic target in the progression from endometriosis to ovarian cancer.

BACKGROUND

Endometriosis (EMS) is a common chronic gynecological disorder that increases the risk of ovarian cancer by approximately threefold. However, the molecular mechanisms underlying this association remain unclear.

METHODS

Mendelian randomization analysis was used to identify the causal relationship between EMS and ovarian cancer. Differential gene expression analysis was conducted using the cancer genome atlas (TCGA) dataset, grouping samples based on miR-874 expression. EcoTyper analysis was applied to evaluate tumor microenvironment composition concerning miR-874 expression. Weighted gene co-expression network analysis (WGCNA) and miWalk target prediction were used to identify key regulatory targets of miR-874. Single-cell RNA sequencing (scRNA-seq) analysis and ChIP-Seq data mining further elucidated the role of miR-874 in clear cell ovarian cancer (CCOC) pathogenesis.

RESULTS

EMS is a key risk factor for CCOC. Multi-datasets analysis revealed that miR-874 down-regulation is closely associated with EMS occurrence, ovarian cancer progression, and patient survival. A total of 194 differentially expressed genes were identified between the high and low miR-874 expression groups, with key genes such as ASB9, TMSB10P1, SMIM24, and PDLIM4 showing significant changes. Functional analysis revealed enrichment in pathways related to mitochondrial function, cell adhesion, proteasomal degradation, and p53 signaling. Survival analysis demonstrated that down-regulation of genes in the high miR-874 group (ZNF623, NDRG1, ZNF7, MTBP, and PHF20L1) was associated with better prognosis, while up-regulation of genes (PDLIM4 and ECRG4) correlated with poorer survival. EcoTyper analysis identified significant tumor microenvironment changes in the high miR-874 group, with an increased abundance of myoepithelial-like (Endothelial.cells.5) and myofibroblast-like (Fibroblasts.1) cells, and reduced levels of migratory-like fibroblasts (Fibroblasts.8), suggesting a more benign tumor phenotype. WGCNA and miWalk analyses indicated that ZNF217 and NDRG1 are potential regulatory targets of miR-874. scRNA-seq data suggested that ZNF217 and NDRG1 are predominantly expressed in ovarian stromal and immune cells. Further, ChIP-Seq data suggest that ZNF217 may bind to the MTBP promoter, which is associated with the stabilization of MDM2, a key negative regulator of p53. We propose a hypothetical miR-874–ZNF217–MTBP–MDM2–p53 regulatory axis that may contribute to the progression of CCOC.

CONCLUSION

The down-regulation of miR-874 may be involved in the progression from EMS to CCOC. We propose that miR-874 may act as a tumor suppressor in CCOC, potentially through the miR-874–ZNF217–MTBP–MDM2–p53 regulatory axis. This proposed mechanism warrants further experimental validation. Collectively, these results provide preliminary insights into the molecular pathogenesis of EMS-associated CCOC and may inform future efforts to identify prognostic markers and therapeutic targets.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s12672-025-03587-9.