Exosome-transferred hsa_circ_0014235 promotes DDP chemoresistance and deteriorates the development of non-small cell lung cancer by mediating the miR-520a-5p/CDK4 pathway

• Published in: Cancer cell international 2020-11, Vol.20 (1), p.1-552, Article 552
• Main Authors: Xu, Xueliang, Tao, Rong, Sun, Liying, Ji, Xia
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomarkers; CDK4; Cell cycle; Cell growth; Cell migration; Cell proliferation; Chemoresistance; Cholecystokinin; Cisplatin; Colonies; Cyclin-dependent kinase 4; Cyclin-dependent kinases; Drug resistance; Exosome; Exosomes; Flow cytometry; Gene expression; hsa_circ_0014235; Immunoprecipitation; Kinases; Lung cancer; Membranes; MicroRNAs; Microscopy; miR-520a-5p; Morphology; Non-small cell lung carcinoma; NSCLC; Polymerase chain reaction; Primary Research; Proteins; Ribonucleic acid; RNA; Small cell lung carcinoma; Transmission electron microscopy; Wound healing
• ISSN: 1475-2867; 1475-2867
• DOI: 10.1186/s12935-020-01642-9

Background Circular RNAs (circRNAs) play crucial roles in the development and progression of human cancers, including non-small cell lung cancer (NSCLC). However, most of these circRNAs, such as hsa_circ_0014235, are not fully identified in functions and mechanisms. Methods The isolated exosomes from serum specimens were identified using transmission electron microscopy (TEM). The expression of hsa_circ_0014235, miR-520a-5p and cyclin-dependent kinase 4 (CDK4) was detected by real-time quantitative polymerase chain reaction (qPCR). For functional assays, cell proliferation, colony formation ability, migration, invasion, cell apoptosis and cell cycle progression were determined using cell counting kit-8 (CCK-8) assay, colony formation assay, wound healing assay, transwell assay and flow cytometry assay, respectively. The expression of CDK4 and other indicated marker proteins was detected by western blot. The predicted target relationship between miR-520a-5p and hsa_circ_0014235 or cyclin-dependent kinase 4 (CDK4) was verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP) assay. Results The expression of hsa_circ_0014235 was notably elevated in NSCLC serum-derived exosomes, tumor tissues and cells. NSCLC serum-derived exosomes promoted NSCLC cell resistance to cisplatin (DDP), cell proliferation, migration and invasion in vitro, as well as tumor growth and DDP resistance in vivo. Hsa_circ_0014235 overexpression enhanced DDP resistance and facilitated cell malignant behaviors. MiR-520a-5p was a target of hsa_circ_0014235, and rescue experiments showed that miR-520a-5p restoration reversed the effects of hsa_circ_0014235 overexpression. Moreover, CDK4 was a target of miR-520a-5p, and rescue experiments showed that CDK4 knockdown reversed the aggressive effects of miR-520a-5p inhibition on NSCLC progression. Conclusions Exosome-transmitted hsa_circ_0014235 promoted NSCLC malignant development by mediating the miR-520a-5p/CDK4 regulatory axis.