Circ72309 modulates gemcitabine metabolism and gemcitabine sensitivity in pancreatic cancer: Serum Circ72309 levels as a potential predictor of treatment response

Circular RNAs (circRNAs) are associated with various biological features of cancer, including chemosensitivity and the structural characteristics of circRNAs indicate their potential as liquid biomarkers. Gemcitabine is a cornerstone treatment for pancreatic cancer (PC). A deeper understanding of gemcitabine sensitivity and the exploration of clinically valuable liquid biomarkers that are predictive of gemcitabine sensitivity may contribute to the development of improved‑tailored treatment strategies for PC. The aim of the present study was to identify a candidate circRNA associated with gemcitabine sensitivity, investigate its biological functions and evaluate its potential as a liquid biomarker in predicting gemcitabine sensitivity. circRNA sequencing analysis was conducted to identify candidate circRNAs and the function of a candidate circRNA in modulating gemcitabine sensitivity was investigated in vitro. Further, the potential of this circRNA in predicting gemcitabine sensitivity in patients with PC who received gemcitabine‑based neoadjuvant chemotherapy was evaluated using pre‑treatment serum samples. circ72309 was identified as the candidate circRNA and its overexpression in gemcitabine‑resistant PC cell lines increased gemcitabine‑induced apoptosis and markedly increased gemcitabine sensitivity in vitro. Furthermore, circ72309 decreased cytidine deaminase by increasing reactive oxygen species activity and increasing human equilibrative nucleoside transporter 1 expression via regulation of target miRNAs. Patients with high serum circ72309 had markedly improved progression‑free survival (PFS) and high serum circ72309 was an independent prognostic predictor of a favorable PFS in patients with PC. circ72309 affected multiple steps in the gemcitabine metabolic pathway and its overexpression resulted in markedly increased gemcitabine sensitivity. Therefore, circ72309 expression in the pre‑treatment serum samples may serve as a predictor of gemcitabine sensitivity in patients with PC.