Wang Y, Xia H, Zhuang Z, Miao L, Chen X, Cai H
Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.
1] Yijishan Hospital, Wannan Medical College, Wuhu, China [2] School of Medicine, Jinan University, Guangzhou, China.
Cell Death Dis. 2014 May 15;5(5):e1227. doi: 10.1038/cddis.2014.186.
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.
Axl激酶参与非小细胞肺癌（NSCLC）对酪氨酸激酶抑制剂（TKIs）吉非替尼或厄洛替尼获得性耐药的现象最近已被发现，但Axl导致TKI耐药的机制仍 largely未知。微小RNA（miRNA）可抑制基因表达，其在肿瘤发生中的关键作用已被证实。为了研究miRNA在Axl介导的吉非替尼获得性耐药中的作用，我们检测了吉非替尼耐药肺癌中Axl介导的miRNA变化。鉴定出一组Axl激酶改变的miRNA。在本研究中，我们验证并报告，由Axl调节的miR-374a和miR-548b分别通过靶向Wnt5a和CCNB1基因，在体外和体内对吉非替尼耐药肺癌细胞的细胞周期阻滞、吉非替尼诱导的凋亡、上皮-间质转化、迁移和肿瘤发生中起重要作用。具有临床意义的是，Axl和miR-374a的高表达以及miR-548b的低表达与术后无病生存期差相关。这些发现表明，特定miRNA的调节可能为未来治疗或逆转Axl高表达的NSCLC中的吉非替尼耐药提供治疗靶点。
