CircFoxo3 Promotes Adriamycin Resistance Through Regulation of miR-199a-5p/ATP Binding Cassette Subfamily C Member 1 Axis in Hepatocellular Carcinoma

Introduction: Chemotherapy resistance is the main cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Therefore, it is important to understand the molecular mechanism of adriamycin (ADM) resistance in HCC. Increasing evidence indicates that circular RNAs (circRNAs) play a crucial regulatory role in different pathological processes. In the current study, we aimed to investigate the roles and the underlying molecular mechanism of circFoxo3 in ADM-resistant HCC. Materials and Methods: Twenty-five pairs of clinical tumors samples and matched normal tissues were collected from patients with HCC. Gain- and loss-function experiments were performed to investigate the role of circFoxo3 in ADM-resistant cells. Results: CircFoxo3 expression was increased in ADM-resistant HCC tissues and HCC cell lines and in metastatic tissues compared with non-metastatic tissues. CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth. In addition, circFoxo3 interacted with miR-199a-5p and regulated miR-199a-5p expression. Furthermore, ATP Binding Cassette Subfamily C Member 1 (ABCC1) was identified as a new target of miR-199a-5p. CircFoxo3 interacted with miR-199a-5p to positively regulate ABCC1 expression, contributing to epithelial-mesenchymal transition progression. Conclusion: CircFoxo3 knockdown reduces and circFoxo3 overexpression enhances HCC cell invasion and tumor growth through regulation of miR-199a-5p/ABCC1 axis. Our findings reveal that circFoxo3 may be novel biomarkers and therapeutic target for HCC treatment.