Construction of a circRNA-miRNA-mRNA ceRNA regulatory network identifies RNAs and genes linked to human ovarian clear cell carcinoma

Abstract

Background: Ovarian clear cell carcinoma (OCCC) is an aggressive epithelial ovarian cancer subtype that prevalent in East Asia. Competing endogenous RNA (ceRNA) networks involving circular RNAs (circRNAs) and microRNAs (miRNAs) represent underexplored regulatory layers in OCCC pathogenesis.

Methods: Multi-omics integration of circRNA (GSE271851 and GSE266248) and miRNA (GSE230956 and GSE200852) datasets from GEO was performed using DESeq2 and limma tools (|log2FC|≥1, p<0.05). Experimentally validated circRNA-miRNA interactions were predicted using circBank 2.0, Circular RNA Interactome, and Starbase v3.0. ceRNA networks were constructed using inverse correlation principles and visualized in Cytoscape. Immune associations were assessed using TIMER2.0. Prognostic and expression validations were performed using the Kaplan-Meier Plotter and HPA databases, respectively.

Results: Three core circRNAs (hsa_circ_0002822, hsa_circ_0003641 and hsa_circ_0030509) were identified as being dysregulated across OCCC models. Their miRNA sponging activity formed a 65-node ceRNA network involving 15 miRNAs (e.g., miR-143-3p and miR-182-5p) and 47 mRNAs. Six targets (BRCA1, KRAS, MSH6, SMARCA4, SRC, and TSC1) exhibited significant correlations with immune infiltration (CD8⁺ T cells, Tregs, and MDSCs). High expression of BRCA1, KRAS, and MSH6 predicted poor survival, with protein-level upregulation confirmed in OCCC tissues.

Conclusion: This study delineates a circRNA-driven ceRNA network in OCCC, and identifies BRCA1, KRAS, and MSH6 as multi-omic biomarkers with immune-modulatory roles. These findings provide a basis for the development of RNA-targeted therapies against this ovarian cancer subtype.

Keywords: ceRNA network; circRNA; immune infiltration; ovarian clear cell carcinoma; prognostic biomarker.