The biomarker potential of circPOLD1 and its binding protein YBX1 in cervical carcinogenesis

Cervical cancer progresses through distinct precancerous stages, making early screening and intervention crucial for prevention. However, conventional screening modalities, such as cytology and HPV testing, face challenges related to sensitivity, specificity, and resource dependency. Circular RNAs (circRNAs), owing to their high stability and tissue-specific expression, have emerged as promising biomarkers, though their role in cervical carcinogenesis remains underexplored. In particular, the clinical utility of circRNAs for optimizing cervical cancer screening and early diagnosis has yet to be established. This study aimed to investigate the dynamic expression profiles of circRNAs across various stages of cervical cancer progression and identify potential biomarkers to enhance early detection.

CircRNA sequencing was performed on cervical tissues spanning normal cervical epithelium (NCE), high-grade squamous intraepithelial lesions (HSIL), and cervical squamous cell carcinoma (CSCC). Functional assays, including cell viability, colony formation, and apoptosis, were performed to assess the oncogenic potential of circPOLD1 and its interaction with YBX1 in cervical cancer cells. BaseScope and immunohistochemistry (IHC) were applied to tissue microarrays for clincial validation and ROC curve analysis evaluated the diagnostic performance of circPOLD1 in serum as a liquid biopsy marker.

CircRNA profiling revealed a progressive increase in circPOLD1 expression from NCE to HSIL and CSCC. Mechanistically, circPOLD1 functioned as an oncogene by binding to and phosphorylating YBX1, activating the AKT/mTOR/HIF-1α pathway to enhance glycolysis-driven tumorigenesis. BaseScope and IHC confirmed the stage-specific elevation of circPOLD1 and YBX1 in cervical lesions. The circPOLD1/YBX1 multi-marker panel demonstrated superior diagnostic performance, achieving an AUC of 0.951 for LSIL+ and 0.817 for HSIL+ detection. Furthermore, serum circPOLD1 levels exhibited a progressive increase across disease stages, underscoring its potential as a non-invasive biomarker.

circPOLD1 and YBX1 synergistically drive cervical carcinogenesis and exhibit stage-specific expression patterns. Their combined detection significantly enhanced the accuracy for cervical cancer screening and dynamic monitoring. The successful application of BaseScope and IHC highlights the immediate translational potential of these biomarkers, paving the way for refined risk stratification, improved therapeutic targeting, and reduced cervical cancer burden through early intervention.