circARHGAP5 inhibits cisplatin resistance in cervical squamous cell carcinoma via interacting with AUF1.

Cervical squamous cell carcinoma (CSCC) is one of the leading causes of cancer death in women worldwide. Patients with advanced cervical carcinoma always have a poor prognosis once resistant to cisplatin due to the lack of effective treatment. It is urgent to investigate the molecular mechanisms of cisplatin resistance. Circular RNAs (circRNAs) are known to exert their regulatory functions in a series of malignancies. However, their effects on CSCC remain to be elucidated. Here, we identified cytoplasmic circARHGAP5, derived from second and third exons of ARHGAP5 gene, was downregulated in cisplatin resistant tissues compared with the normal cervix tissues and untreated cervical cancer tissues. In addition, experiments from overexpression/knockdown cell lines revealed that circARHGAP5 could inhibit cisplatin (CP) mediated cell apoptosis in CSCC cells both in vitro and in vivo. Mechanistically, circARHGAP5 interacted with AU-rich element RNA-binding protein AUF1 directly. Overexpression of AUF1 could also inhibit cell apoptosis mediated by cisplatin. Furthermore, we detected the potential targets of AUF1 related to apoptotic pathway and found that BIM was not only negatively regulated by AUF1 but positively regulated by circARHGAP5, which indicated that BIM mRNA might be degraded by AUF1 and thereby inhibited tumor cell apoptosis. Collectively, our data demonstrated that circARHGAP5 directly bound to AUF1 and prevented AUF1 from interacting with BIM mRNA, played a pivotal role in the cisplatin resistance in CSCC, which may provide insights into overcoming cancer resistance to cisplatin treatment.