Folia Biologica
Journal of Cellular and Molecular Biology, Charles University 

With a dismal prognosis, cholangiocarcinoma (CCA) is a highly invasive cancer and its global incidence is increasing. Non-coding RNAs, particularly circRNAs, are increasingly recognized as important regulators in tumorigenesis, yet the mechanistic details of hsa_circ_0000977-mediated miR-338-3p regulation in CCA remain incompletely understood. This study aimed to investigate the mechanism of the hsa_circ_0000977/miR-338-3p/ETS1 axis in CCA progression, evaluate its prognostic significance and investigate its functional role in CCA cells. Real-time quantitative PCR (RT-qPCR) was performed to quantify hsa_circ_0000977, miR-338-3p and ETS1 mRNA expression levels. Pearson correlation was used to assess their association. To confirm the molecular interactions between these molecules, dual-luciferase reporter assays were employed. Cell migration capacity was evaluated via Transwell migration assays, while CCK-8 tests analysed proliferation. Prognostic value was assessed through survival analysis and multi­variate regression. The study revealed significant up-regulation of hsa_circ_0000977 in CCA tumour tissues, with elevated expression levels associated with poorer 5-year survival outcomes. Multivariate analysis confirmed that hsa_circ_0000977 over-expression is an independent predictor of survival. Functional assays indicated that hsa_circ_0000977 negatively regulated miR-338-3p, which was down-regulated in CCA and exhibited tumour-suppressive effects. CCA cell proliferation and migration were suppressed following hsa_circ_0000977 knockdown, effects that were partially reversed by miR-338-3p inhibition. Further investigation demonstrated that miR-338-3p exerts its tumour-suppressive effects by directly targeting ETS1, and the hsa_circ_0000977/miR-338-3p/ETS1 axis regulates the proliferation and migration of CCA cells. We have concluded that hsa_circ_0000977 drives CCA progression by sponging miR-338-3p and modulating its target ETS1, suggesting its clinical value for predicting outcomes and developing targeted therapies.

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