机构：[1]Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China[2]Yijishan Hospital, Wannan Medical College, Wuhu, China[3]School of Medicine, Jinan University, Guangzhou, China[4]Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China[5]Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
The involvement of Axl kinase in non-small cell lung cancer's (NSCLC) acquired resistance to tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib has been identified recently, but the mechanism by which Axl contributes to TKI resistance is largely unknown. MicroRNAs (miRNAs) repress gene expression and their critical role in tumorigenesis has been implicated. To investigate the role of miRNAs in the Axl-mediated acquired gefitinib resistance, we examined the Axl-mediated miRNA changes in gefitinib-resistant lung cancers. A panel of Axl kinase-altered miRNAs was identified. In this study, we validate and report that miR-374a and miR-548b modulated by Axl have essential roles in cell cycle arrest, gefitinib-induced apoptosis, epithelial-to-mesenchymal transition, migration and tumorigenesis of gefitinib-resistant lung cancer cells in vitro and in vivo by targeting Wnt5a and CCNB1 genes, respectively. Of clinical significance, high expression of Axl and miR-374a and low expression of miR-548b are associated with poor disease-free survival postoperatively. These findings indicate that the modulation of specific miRNAs may provide a therapeutic target to treat or reverse gefitinib resistance in NSCLC with high expression of Axl in the future.
基金：
This work was supported by grants from the National Natural Science Foundation of China; Grant Number: 81301882, 81172240.
第一作者机构：[1]Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China
共同第一作者：
通讯作者：
通讯机构：[*1]Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.[*2]Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, China.
推荐引用方式(GB/T 7714)：
Y Wang,H Xia,Z Zhuang,et al.Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer[J].CELL DEATH & DISEASE.2014,5(5):e1227.doi:10.1038/cddis.2014.186.
APA：
Y Wang,H Xia,Z Zhuang,L Miao,X Chen&H Cai.(2014).Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer.CELL DEATH & DISEASE,5,(5)
MLA：
Y Wang,et al."Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer".CELL DEATH & DISEASE 5..5(2014):e1227
生物学