CircRNA_100565 contributes to cisplatin resistance of NSCLC cells by regulating proliferation, apoptosis and autophagy via miR-337-3p/ADAM28 axis.

Abstract

Circular RNAs (circRNAs) have been revealed to involve in the chemoresistance of various cancers, including non-small cell lung cancer (NSCLC). Here, we further investigate the role of circRNA_100565 in NSCLC cisplatin (DDP) resistance. The expression of circRNA_100565 and microRNA (miR)-337-3p, and ADAM metallopeptidase domain 28 (ADAM28) mRNA was detected using quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit-8 assay and flow cytometry, respectively. Western blot was used to detect the level of ADAM28 and autophagy-related protein. The interaction between miR-337-3p and circRNA_100565 or ADAM28 was confirmed by dual-luciferase reporter assay or pull-down assay. In vivo experiments were conducted via the murine xenograft model. We found CircRNA_100565 was up-regulated in NSCLC DDP-resistant tissues and cell lines, and its high expression was associated with shorter overall survival of NSCLC patients. CircRNA_100565 deletion mitigated DDP resistance, reflected by the suppression of proliferation and autophagy, the reduction of IC50 value, as well as enhancement of apoptosis in DDP-resistant NSCLC cells. MiR-377-3p was confirmed to directly bind to circRNA_100565 or ADAM28 3'-UTR. Moreover, circRNA_100565 indirectly regulated ADAM28 expression by sponging miR-377-3p in NSCLC cells. Additionally, circRNA_100565 deletion-induced sensitivity of NSCLC resistant cells to DDP could be remarkably attenuated by miR-377-3p inhibition or ADAM28 re-expression. Meanwhile, circRNA_100565 knockdown contributed to the anti-tumor effects of DDP on NSCLC in vivo.CONCLUSION: CircRNA_100565 was an independent prognostic factor for NSCLC patient survival, and enhanced the resistance of NSCLC cells to cisplatin by regulating cell proliferation, apoptosis and autophagy via miR-337-3p/ADAM28 axis, shedding light on the development of a novel therapeutic strategy to boost the effectiveness of NSCLC chemotherapy.