Exploring the role of circRNA-miRNA-mRNA interactions in cervical cancer progression: insights into HPV status and potential therapeutic approaches.

Human papillomavirus (HPV) is the primary etiological factor in cervical cancer. Circular RNAs (circRNAs) contribute significantly to tumor progression, functioning as microRNA (miRNA) sponges and interacting with RNA-binding proteins (RBPs). While circRNA-miRNA-mRNA regulatory networks have been studied in cervical cancer, the lack of intermediate neoplastic samples has limited the understanding of circRNA-driven progression from HPV-positive (HPV ⁺) or HPV-negative (HPV ^-) normal cervical epithelium (NCE) to cervical squamous cell carcinoma (CSCC). This study addressed that gap by identifying differentially expressed (DE) circRNAs across four comparisons: high-grade squamous intraepithelial lesions (HSIL) vs. HPV ⁺ NCE, HSIL vs. HPV ^-NCE, CSCC vs. HPV ⁺NCE, and CSCC vs. HPV ^- NCE, using the limma R package. Commonly dysregulated circRNAs across comparisons were identified, revealing potential contributors to cancer progression regardless of HPV status. Of the 12 DE circRNAs identified, 11 had miRNA partners predicted via circAtlas, implicated in various oncogenic pathways. A protein-protein interaction (PPI) network of 30 hub genes was generated using STRING analysis. Among these, USP39, PQBP1, ANAPC5, STUB1, and UBE2D2 were significantly associated with overall survival in cervical cancer. Validation using qRT-PCR confirmed a competing endogenous RNA (ceRNA) network involving hsa-KIF4A_0022, hsa-miR-29b-2-5p, and UBE2D2 in cervical cancer of South Asian Indian origin. The study utilized CMAP2 and CTDBASE, identifying foretinib, TPCA-1, and dequalinium as promising drugs targeting key hub genes. Although limitations include a small sample size and ethnic heterogeneity in in vitro validation, this study advances our understanding of circRNA mechanisms in cervical cancer and identifies novel biomarkers and therapeutic targets.