Exploring a circulating circRNA and miRNA biomarker panel for early detection of ovarian cancer through multiple omics analysis

Abstract

Abstract The biological functions of circular RNA (circRNAs) in cancers have garnered significant attention, particularly for their potential as biomarkers. However, the roles of circRNAs in ovarian cancer (OC) and their applicability for early detection of this malignancy remain underexplored. We performed RNA sequencing on ovarian cancer cell lines to identify circRNAs associated with OC. The functional mechanisms of the identified circRNAs were elucidated through bioinformatics analysis. The discriminating ability of biomarkers was assessed using receiver operating characteristic (ROC) analysis. RNA sequencing analysis revealed that 170 known circRNAs were correlated with ovarian cancer. Through the circRNA-miRNA-mRNA regulatory network, we identified 9 circRNAs that interact with 8 miRNAs, subsequently regulating the expression of 324 mRNAs. Functional enrichment analysis, protein-protein interaction (PPI) network analysis, and hub gene analysis indicated that these circRNAs and miRNAs may play a role in regulating MAPK, Wnt, and ErbB signaling pathways. We validated these circRNAs and miRNAs expression profiles in cell, tissue, and plasma samples, identifying four candidates—hsa_circ_0049101, hsa_circ_0007440, hsa_circ_0006935, and hsa-miR-338-3p—that expression level positively correlate with ovarian cancer development. These markers were then combined into a circRNA and miRNA detection (CMD) panel for ovarian cancer detection. The area under the curve (AUC) values obtained from ROC analysis demonstrated that these individual candidates, as well as the CMD panel, exhibited superior discriminatory ability for OC compared to traditional biomarkers such as CA125, HE4, and the ROMA index in our sample set, which included 28 healthy controls and 22 ovarian cancer patients. Notably, the CMD panel showed exceptional potential for distinguishing early-stage OC samples from healthy controls, achieving an AUC of 1. In this study, we elucidated the functional mechanisms of a set of circRNAs associated with OC through multi-omics analysis and demonstrated that the combination of circRNAs and miRNAs into a biomarker panel holds significant potential for early detection of ovarian cancer.

Keywords

• Ovarian cancer
• Biomarker
• CircRNA-miRNA panel
• Bioinformatics
• Clinical early detection