Hypoxia-induced antizyme inhibitors 2 regulates cisplatin resistance through epithelia-mesenchymal transition pathway in non-small cell lung cancer

Abstract

Antizyme inhibitors 2 (AZIN2) was found to be associated with poor prognosis of patients with rectal cancer. However, no studies have reported whether AZIN2 functions in non-small cell lung cancer (NSCLC). This study aimed to investigate the role of AZIN2 in cisplatin (DDP) resistance in NSCLC. We established DDP resistant A549 and H1299 cell lines. The transcriptional and translational expression levels were examined using quantitative real-time polymerase chain reaction and western blot. Cell apoptosis was evaluated by caspase-3 activity and nucleosome ELISA assays. Luciferase reporter assay was employed to evaluate the impact of hypoxia-inducible factor (HIF-1α) on AZIN2 transcription. AZIN2 expression was found to be associated with DDP resistance and poor prognosis in patients with NSCLC. AZIN2 overexpression promoted cell viability, colony formation, and reduced cell apoptosis in H1299 cells and A549 upon DDP treatment. Correspondingly, AZIN2 knockdown significantly inhibited cell viability and colony formation, and increased cell apoptosis upon DDP treatment. Interestingly, AZIN2 expression in NSCLC cells was significantly induced by hypoxia condition. The occupancy of HIF-1α, an important regulator of the hypoxia response, remarkably enriched at the promoter region of AZIN2 under hypoxia condition. In addition, AZIN2 overexpression resulted in epithelial–mesenchymal transition (EMT). The results suggested that hypoxia-induced AZIN2 high expression may contribute to DDP resistance development by promoting the EMT.