MiR-224 promotes the chemoresistance of human lung adenocarcinoma cells to cisplatin via regulating G1/S transition and apoptosis by targeting p21WAF1/CIP1

Background: Increasing evidence has shown that microRNAs (miRNAs) can serve as oncogenes and tumour suppressors to participate in tumour development. However, the roles of miRNAs in chemoresistance of human lung adenocarcinoma (LA) remain largely undefined. Methods: On the basis of miRNA microarray data, miR-224 was identified as the most upregulated miRNA in cisplatin (DDP; cis-diamminedichloroplatinum II)-resistant A549 cells compared with parental A549 cells. The aim of our study was to investigate the roles of miR-224 in the formation of DDP-resistant phenotype of LA cells and its possible molecular mechanisms. Results: Here we showed that miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G(1)/S cell cycle transition and apoptosis. p21(WAF1/CIP1), a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21(WAF1/CIP1) could phenocopy the effect of miR-224 downregulation and silencing of p21(WAF1/CIP1) could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G(1)/S transition of cell cycle and apoptosis in LA cells through the p21(WAF1/CIP1)-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21(WAF1/CIP1). Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients. Conclusions: Our findings shed novel light on the roles of miR-224/p21(WAF1/CIP1) signalling in the DDP resistance of LA cells, and targeting it will be a potential strategic approach for reversing the DDP resistance in human LAs.