title: Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells.
abstract: Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial-mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors: Wei-Hsiu
authors: WH
authors: Liu
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital & National Yang-Ming University, Taipei, Taiwan.
authors: Ming-Teh
authors: MT
authors: Chen
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Mong-Lien
authors: ML
authors: Wang
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yi-Yen
authors: YY
authors: Lee
authors: College of Biological Science and Technology, National Chiao Tung Univeristy, Taiwan.
authors: Guang-Yuh
authors: GY
authors: Chiou
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan.
authors: Chian-Shiu
authors: CS
authors: Chien
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Pin-I
authors: PI
authors: Huang
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yi-Wei
authors: YW
authors: Chen
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Pediatric Neurosurgery, Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Ming-Chao
authors: MC
authors: Huang
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan.
authors: Shih-Hwa
authors: SH
authors: Chiou
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital & National Yang-Ming University, Taipei, Taiwan.
authors: Yang-Hsin
authors: YH
authors: Shih
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.|Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
authors: Hsin-I
authors: HI
authors: Ma
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018335:Rhabdoid Tumor / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D002945:Cisplatin
references: Nat Rev Drug Discov. 2006 Mar;5(3):219-34
references: 16518375
references: Zhonghua Wei Chang Wai Ke Za Zhi. 2014 Jun;17(6):594-7
references: 24953370
references: Nat Rev Cancer. 2007 Jun;7(6):415-28
references: 17508028
references: BMC Cancer. 2012;12:91
references: 22429801
references: Nature. 2012 Aug 23;488(7412):522-6
references: 22854781
references: Stem Cells. 2014 Oct;32(10):2571-82
references: 24891218
references: J Neurooncol. 2005 Dec;75(3):279-85
references: 16195802
references: Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4147-53
references: 16857785
references: Cancer Res. 2013 Jul 1;73(13):3852-64
references: 23633489
references: J Clin Oncol. 2004 Jul 15;22(14):2877-84
references: 15254056
references: Front Oncol. 2012 Sep 12;2:114
references: 22988546
references: Cancer Lett. 2012 Dec 1;325(1):42-53
references: 22652173
references: Cancer Res. 2006 Sep 1;66(17):8319-26
references: 16951136
references: Anticancer Res. 1982 May-Jun;2(3):173-86
references: 6751211
references: Cancer Res. 2005 Oct 1;65(19):8927-35
references: 16204065
references: Tumour Biol. 2014 Jul;35(7):7097-103
references: 24760274
references: Blood. 1998 Mar 1;91(5):1700-5
references: 9473236
references: Cancer Lett. 2013 Dec 1;341(2):231-9
references: 23962558
references: J Clin Oncol. 2009 Jan 20;27(3):385-9
references: 19064966
references: Mol Carcinog. 2015 Jun;54 Suppl 1:E81-93
references: 24976450
references: Cancer Sci. 2013 Jul;104(7):904-11
references: 23566288
references: Int J Oncol. 2014 May;44(5):1643-51
references: 24573038
references: BMC Cancer. 2011;11:49
references: 21284870
references: Chin J Cancer. 2010 Feb;29(2):167-71
references: 20109345
references: Mol Cancer Ther. 2008 Oct;7(10):3169-75
references: 18852120
references: Neuroradiology. 2008 May;50(5):447-52
references: 18345534
references: Oncotarget. 2012 Sep;3(9):1036-48
references: 23013619
references: Nat Rev Cancer. 2002 Mar;2(3):221-5
references: 11990858
references: Oncogene. 2012 Jan 26;31(4):432-45
references: 21725369
references: Nat Cell Biol. 2008 Feb;10(2):127-37
references: 18204440
references: Curr Pharm Biotechnol. 2011 Apr;12(4):570-94
references: 21118094
references: J Neurooncol. 2005 Mar;72(1):77-84
references: 15803379
references: ACS Med Chem Lett. 2013 Sep 08;4(11):1102-7
references: 24900612
references: JAKSTAT. 2014 Jan 1;3(1):e28975
references: 24843831
references: J Neurooncol. 2012 Jan;106(2):281-90
references: 21842312
references: Int J Clin Exp Pathol. 2014;7(5):2372-81
references: 24966947
references: J Clin Invest. 2014 Apr;124(4):1853-67
references: 24642471
references: Oncol Lett. 2013 Dec;6(6):1619-1623
references: 24260055
references: Nat Cell Biol. 2005 Mar;7(3):255-61
references: 15723050
references: Nat Rev Cancer. 2004 Feb;4(2):97-105
references: 14964307
references: Mod Pathol. 2005 Jun;18(6):769-78
references: 15776015
references: Cancer Res. 2013 Jun 1;73(11):3425-40
references: 23548270
references: Neoplasia. 2008 Jul;10(7):736-44
references: 18592012
references: Int J Oncol. 2014 Jul;45(1):165-76
references: 24806843
references: J Hepatol. 2011 Oct;55(4):838-45
references: 21334406
references: Cancer Med. 2014 Feb;3(1):91-100
references: 24402832
references: Mol Cancer Res. 2013 Jan;11(1):31-42
references: 23074171
references: Cell Cycle. 2005 Dec;4(12):1693-8
references: 16294046
references: Mol Pharm. 2012 Nov 5;9(11):3147-59
references: 23046348
references: J Cell Biochem. 2011 Oct;112(10):2850-64
references: 21618587
references: Mol Cancer Res. 2011 Dec;9(12):1658-67
references: 21976712
references: Pediatr Blood Cancer. 2014 Jan;61(1):120-7
references: 23956023
references: Cancer Res. 2007 Oct 1;67(19):9066-76
references: 17909010
references: Stem Cells. 2009 Sep;27(9):2059-68
references: 19544473
references: J Biol Chem. 2012 Feb 17;287(8):5819-32
references: 22205702
references: Cell. 2012 Mar 2;148(5):1015-28
references: 22385965
references: EMBO Mol Med. 2013 Aug;5(8):1196-212
references: 23818228
references: PLoS One. 2013;8(1):e54193
references: 23349823
references: Pharmacol Rev. 2012 Jul;64(3):706-21
references: 22659329
references: Cancer Cell. 2004 Jan;5(1):13-7
references: 14749122
references: Cell Transplant. 2014;23(4-5):669-90
references: 24816458
references: Am J Surg Pathol. 1998 Sep;22(9):1083-92
references: 9737241
references: Recent Pat Anticancer Drug Discov. 2006 Jun;1(2):285-95
references: 18221042
references: Eur J Pharmacol. 2014 Jan 15;723:156-66
references: 24333218
references: PLoS One. 2008;3(5):e2090
references: 18509505
references: Clin Cancer Res. 2010 Sep 15;16(18):4561-71
references: 20823140
references: Biochem Biophys Res Commun. 2011 Mar 25;406(4):643-8
references: 21371437