A Novel Circular RNA hsa_circRNA_103809/miR-377-3p/GOT1 Pathway Regulates Cisplatin-Resistance in Non-Small Cell Lung Cancer (NSCLC)
Abstract Cisplatin is the first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC), and emerging evidences suggested that targeting circular RNAs (circRNAs) became an effective strategy to increase cisplatin-sensitivity in NSCLC, but the detailed mechanisms are still not fully delineated. Based on this, this study identified a novel hsa_circRNA_103809/miR-377-3p/GOT1 signaling cascade contributed to cisplatin-resistance in NSCLC in vitro and in vivo. Mechanistically, the parental cisplatin-sensitive NSCLC (CS-NSCLC) cells were subjected to continuous low-dose cisplatin stimulation to generate cisplatin-resistant NSCLC (CR-NSCLC) cells, and we found that hsa_circRNA_103809 and GOT1 were upregulated, while miR-377-3p was downregulated in CR-NSCLC cells, instead of CS-NSCLC cells. Further experiments validated that hsa_circRNA_103809 sponged miR-337-3p to upregulate GOT1 in CS-NSCLC cells. Interestingly, the gain- and loss-function experiments validated that knock-down of hsa_circRNA_103809 enhanced the inhibiting effects of cisplatin on cell proliferation and viability, and induced cell apoptosis in CR-NSCLC cells, which were reversed by downregulating miR-377-3p and overexpressing GOT1. Consistently, overexpression of hsa_circRNA_103809 increased cisplatin-resistance in CS-NSCLC cells by regulating miR-377-3p/GOT1 axis. Furthermore, the xenograft tumor-bearing mice models were established by using the CR-NSCLC cells, and we proved that silencing of hsa_circRNA_103809 aggravated the inhibiting effects of cisplatin treatment on NSCLC cell growth in vivo. In general, analysis of data suggested that targeting hsa_circRNA_103809/miR-377-3p/GOT1 pathway increased susceptibility of CR-NSCLC cells to cisplatin, and this study provided novel agents to improve the therapeutic efficacy of cisplatin for NSCLC treatment in clinic.