Circ_0048856 competes with ABCC1 for miR-193a-5p/miR-98-5p binding sites to promote the cisplatin resistance and tumorigenesis in lung cancer

Abstract

Although cisplatin (DDP)-based therapy is the most predominant chemotherapeutic strategy used for lung cancer, drug resistance usually occurs after several cycle use of it. Circular RNAs (circRNAs) are found to be involved in the chemoresistance in lung cancer. Hence, this study aimed to clarify the role and mechanism of circ_0048856 in lung cancer tumorigenesis and DDP resistance. The levels of circ_0048856, miR-193a-5p, miR-98-5p and ABCC1 (ATP Binding Cassette Subfamily C Member 1) were determined by qRT-PCR and western blotting. In vitro assays were conducted by cell counting kit-8 assay, 5-ethynyl-2’-deoxyuridine (EDU) assay, flow cytometry and transwell assay, respectively. The binding interaction was verified using dual-luciferase reporter assay and RIP assay. In vivo experiment was performed by the establishment of murine xenograft model. Circ_0048856 was highly expressed in DDP-resistant lung cancer tissues and cells. Functionally, circ_0048856 silencing re-sensitized DDP-resistant lung cancer cells to DDP, as well as suppressed cell growth and invasion in lung cancer in vitro and in vivo. Mechanistically, circ_0048856 acted as the sponge for miR-193a-5p or miR-98-5p, which targeted ABCC1. Furthermore, rescue experiments showed that inhibition of miR-193a-5p or miR-98-5p reversed the effects of circ_0048856 knockdown on lung cancer cells. Besides that, overexpression of miR-193a-5p or miR-98-5p suppressed cell tumorigenesis and reduced DDP resistance in lung cancer, which were attenuated by ABCC1 up-regulation. Circ_0048856 knockdown suppressed tumor growth and reduced DDP resistance in lung cancer by miR-193a-5p/ABCC1 or miR-98-5p/ABCC1 axis, indicating a novel strategy for efficient application of DDP in lung cancer.