ELF1 suppresses autophagy to reduce cisplatin resistance via the miR-152-3p/NCAM1/ERK axis in lung cancer cells

Abstract

Resistance to chemotherapeutic drugs limits the efficacy of chemotherapy in non-small cell lung cancer (NSCLC). Autophagy is an essential mechanism which involves in drug resistance. Our previous research has revealed that miR-152-3p represses NSCLC progression. However, the mechanism of miR-152-3p in autophagy-mediated chemoresistance in NSCLC remains unclear. Cisplatin-resistant cell lines (A549/DDP and H446/DDP) were transfected with related vectors and subjected to cisplatin, autophagy inhibitor, activator, or extracellular signal-regulated kinase (ERK) activator. Flow cytometry, CCK8 and colony formation assays were performed for testing apoptosis and cell viability. The related RNAs or proteins were detected by qRT-PCR or Western blot. Chromatin immunoprecipitation, luciferase reporter assay or RNA immunoprecipitation were used for validating the interaction between miR-152-3p and ELF1 or NCAM1. Co-IP verified the binding between NCAM1 and ERK. The role of miR-152-3p in cisplatin resistance of NSCLC was also validated in vivo. The results showed that miR-152-3p and ELF1 were decreased in NSCLC tissues. miR-152-3p reversed cisplatin resistance by inhibiting autophagy through NCAM1. NCAM1 promoted autophagy through the ERK pathway and facilitated cisplatin resistance. ELF1 positively regulated miR-152-3p level by directly interacting with miR-152-3p promoter. miR-152-3p targeted NCAM1 to regulate NCAM1 level and then affected the binding of NCAM1 to ERK1/2. ELF1 inhibited autophagy and reversed cisplatin resistance through miR-152-3p/NCAM1. miR-152-3p inhibited autophagy and cisplatin resistance of xenograft tumor in mice. In conclusion, our study revealed that ELF1 inhibited autophagy to attenuate cisplatin resistance through the miR-152-3p/NCAM1/ERK pathway in H446/DDP and A549/DDP cells, suggesting a potential novel treatment strategy for NSCLC.

Keywords: ELF1; NCAM1; autophagy; chemoresistance; miR-152-3p; non-small cell lung cancer.