Circular RNA circ-RNF121 contributes to cisplatin (DDP) resistance of non-small-cell lung cancer cells by regulating the miR-646/SOX4 axis.

Abstract

Chemo-resistance is considered a major obstacle in the clinical treatment of non-small-cell lung cancer (NSCLC). Circular RNA (circRNA) circ-RNF121 (hsa_circ_0023404) has been identified to be related to the cisplatin (DDP) resistance. However, the role and mechanism of circ-RNF121 in the DDP resistance in NSCLC are still unknown. Real-time quantitative PCR (RT-qPCR) was applied to detect the levels of circ-RNF121, microRNA-646 (miR-646) and SRY-related HMG box transcription factor 4 (SOX4). Cell viability, proliferation, apoptosis, migration, invasion and cell cycle progression were assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, flow cytometry, wound-healing, transwell and flow cytometry assays, severally. The binding relationship between miR-646 and circ-RNF121 or SOX4 was predicted by the circular RNA interactome or Target Scan Human7.2 and then verified by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. SOX4 protein level was measured by western blot assay. The biological role of circ-RNF121 on NSCLC tumor growth and drug resistance was examined by the xenograft tumor model in vivo. Circ-RNF121 and SOX4 were increased, and miR-646 was declined in DDP-resistant NSCLC tissues and cells. Furthermore, the circ-RNF121 deficiency could enhance DDP sensitivity by inhibiting cell proliferation, migration, invasion, cell cycle progression and promoting apoptosis in DDP-resistant NSCLC cells in vitro. Mechanically, circ-RNF121 served as a sponge of miR-646 to increase SOX4 expression. Circ-RNF121 knockdown improved the drug sensitivity of NSCLC in vivo. Circ-RNF121 silencing could reduce the DDP resistance of NSCLC cells by regulating SOX4 expression via miR-646. These findings hinted at a promising therapeutic target for NSCLC treatment.