miR-200c regulates crizotinib-resistant ALK-positive lung cancer cells by reversing epithelial-mesenchymal transition via targeting ZEB1.
Crizotinib is an orally administered drug for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non‑small cell lung cancer (NSCLC). Despite the impressive efficacy of crizotinib in the treatment of ALK‑positive lung cancer, acquired resistance eventually develops in the majority of patients. The microRNA (miR)‑200c reverses the resistance of lung cancer cells to various chemotherapeutic drugs and molecular targeted drugs, however, whether it can reverse the resistance of crizotinib remains unknown. The present study established a crizotinib resistant cell line (NCI‑2228/CRI), which was derived from the parental NCI‑2228 cell line by long‑term exposure to increasing concentrations of crizotinib. Through overexpression and suppression of miR‑200c expression, the characteristics associated with epithelial‑mesenchymal transition (EMT), including morphology, EMT marker proteins and cellular mobility, were investigated. Cell viability and invasion assays demonstrated that high expression of miR‑200c significantly inhibited the proliferation, migration and invasion of NCI‑2228 cells compared with the negative control. A luciferase reporter assay indicated that miR‑200c directly targeted the 3'‑untranslated region of zinc finger E‑box binding homeobox 1. Additionally, reverse transcription‑quantitative polymerase chain reaction analysis demonstrated that the mRNA levels of N‑cadherin and Vimentin were decreased in NCI‑2228 cells transfected with miR‑200c mimic compared with negative control cells, whereas the mRNA level of E‑cadherin was increased. In addition, EMT was reversed by miR‑200c, which suggests that miR‑200c may serve a role in mediating the sensitivity of NCI‑2228/CRI cells to crizotinib. The present study may therefore contribute to improving the sensitivity of ALK positive lung cancer cells to crizotinib.
Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Hai-Xiang
HX
Gao
Department of Pulmonology, Hebei General Hospital, Shijiazhuang, Hebei 050081, P.R. China.
Li
L
Yan
Department of Infectious Disease, Hebei General Hospital, Shijiazhuang, Hebei 050081, P.R. China.
Chunzhi
C
Li
Tumor Research Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Lian-Mei
LM
Zhao
Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Wei
W
Liu
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009362:Neoplasm Metastasis; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
Oncol Res. 2014;22(1):47-55
25700358
Int J Oncol. 2014 Oct;45(4):1430-6
25096400
Br J Cancer. 2012 Jan 31;106(3):553-61
22223089
N Engl J Med. 2014 Dec 4;371(23):2167-77
25470694
Cancer Res. 2008 Oct 1;68(19):7846-54
18829540
Cancer Treat Rev. 2014 Jul;40(6):716-22
24759599
Lung Cancer. 2015 Mar;87(3):211-9
25601484
Methods. 2001 Dec;25(4):402-8
11846609
Med Oncol. 2015 Jan;32(1):428
25502084
PLoS One. 2010 Jan 13;5(1):e8697
20084174
Int J Mol Med. 2014 Apr;33(4):879-86
24424572
J Biol Chem. 2008 May 30;283(22):14910-4
18411277
Genes Dev. 2008 Apr 1;22(7):894-907
18381893
Oncogene. 2007 Feb 1;26(5):711-24
16862183
Ann Oncol. 2015 Mar;26(3):451-63
25060421
Arch Pathol Lab Med. 2013 Jun;137(6):828-60
23551194
Oncogene. 2013 Sep 5;32(36):4284-93
23045278
Mol Cancer Ther. 2009 May;8(5):1055-66
19435871
PLoS One. 2013 Oct 30;8(10 ):e78344
24205206
Int J Cancer. 2011 Mar 15;128(6):1327-34
20473948
Cell Death Dis. 2015 Apr 02;6:e1708
25837484
Br J Cancer. 2012 Jan 3;106(1):148-56
22045191
Mayo Clin Proc. 2008 May;83(5):584-94
18452692
Gastroenterology. 2011 Dec;141(6):2140-53
21878201
Oncotarget. 2014 Sep 15;5(17):7902-16
25277203
Clin Cancer Res. 2013 Oct 15;19(20):5602-12
23995857
N Engl J Med. 2010 Oct 28;363(18):1693-703
20979469
Clin Lung Cancer. 2013 Sep;14(5):473-80
23790969
Nat Cell Biol. 2008 May;10 (5):593-601
18376396
Neoplasia. 2013 Feb;15(2):180-91
23441132
Mol Oncol. 2013 Dec;7(6):1093-102
23993685
Mol Biol Cell. 2011 May 15;22(10 ):1686-98
21411626
Clin Cancer Res. 2014 Apr 15;20(8):2029-34
24573551