miR-200/ZEB axis regulates sensitivity to nintedanib in non-small cell lung cancer cells

Autor: Kaoru Kubota, Rintaro Noro, Chie Soeno, Mika Chiba, Masaru Matsumoto, Nobuhiko Nishijima, Masahiro Seike, Teppei Sugano, Akihiko Miyanaga, Akihiko Gemma
Rok vydání: 2015
Předmět:
0301 basic medicine
Cancer Research
Pathology
Indoles
Lung Neoplasms
Cell
chemistry.chemical_compound
0302 clinical medicine
Carcinoma
Non-Small-Cell Lung
nintedanib
Gefitinib
Articles
Cell cycle
miR-200
medicine.anatomical_structure
Phenotype
Oncology
030220 oncology & carcinogenesis
Nintedanib
medicine.drug
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Antineoplastic Agents
Biology
Receptor
Platelet-Derived Growth Factor beta
03 medical and health sciences
Inhibitory Concentration 50
Cell Line
Tumor
EGFR-TKI
microRNA
medicine
Biomarkers
Tumor
Humans
Epithelial–mesenchymal transition
A549 cell
drug resistance
Oncogene
Gene Expression Profiling
Zinc Finger E-box-Binding Homeobox 1
Receptors
Fibroblast Growth Factor
respiratory tract diseases
MicroRNAs
lung cancer
030104 developmental biology
Receptors
Vascular Endothelial Growth Factor
chemistry
Drug Resistance
Neoplasm
Cancer research
Quinazolines
Zdroj: International Journal of Oncology
ISSN: 1791-2423
Popis: Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-β1 exposure of A549 cells. Nintedanib was able to reverse TGF-β1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.
Databáze: OpenAIRE
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