Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer.
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.
Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.
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Wang
1] Yijishan Hospital, Wannan Medical College, Wuhu, China [2] School of Medicine, Jinan University, Guangzhou, China.
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Xia
Department of Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
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Zhuang
Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.
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Miao
Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
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Chen
Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing, China.
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Cai
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D000077156:Gefitinib; D057809:HEK293 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000071818:Wnt-5a Protein; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; C587995:MIRN374 microRNA 374, human; C561887:MIRN548 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D020794:Receptor Protein-Tyrosine Kinases; D000077156:Gefitinib; D000094963:Axl Receptor Tyrosine Kinase