title: STAT3-mediated activation of microRNA cluster 17~92 promotes proliferation and survival of ALK-positive anaplastic large cell lymphoma.
abstract: Systemic anaplastic large cell lymphoma is a category of T-cell non-Hodgkin's lymphoma which can be further subdivided into two distinct entities (ALK(+) and ALK(-)) based on the presence or absence of ALK gene rearrangements. Among several pathways triggered by ALK signaling, constitutive activation of STAT3 is strictly required for ALK-mediated transformation and survival. Here we performed genome-wide microRNA profiling and identified 48 microRNA concordantly modulated by the inducible knock-down of ALK and STAT3. To evaluate the functional role of differentially expressed miRNA, we forced their expression in ALK(+) anaplastic large cell lymphoma cells, and monitored their influence after STAT3 depletion. We found that the expression of the microRNA-17~92 cluster partially rescues STAT3 knock-down by sustaining proliferation and survival of ALK(+) cells. Experiments in a xenograft mouse model indicated that forced expression of microRNA-17~92 interferes with STAT3 knock-down in vivo. High expression levels of the microRNA-17~92 cluster resulted in down-regulation of BIM and TGFβRII proteins, suggesting that their targeting might mediate resistance to STAT3 knock-down in anaplastic large cell lymphoma cells. We speculate that the microRNA-17~92 cluster is involved in lymphomagenesis of STAT3(+) ALCL and that its inhibition might represent an alternative avenue to interfere with ALK signaling in anaplastic large cell lymphomas.
authors: roberto.piva@unito.it or giorgio.inghirami@unito.it.
authors: Elisa
authors: E
authors: Spaccarotella
authors: Elisa
authors: E
authors: Pellegrino
authors: Manuela
authors: M
authors: Ferracin
authors: Cristina
authors: C
authors: Ferreri
authors: Giuditta
authors: G
authors: Cuccuru
authors: Cuiling
authors: C
authors: Liu
authors: Javeed
authors: J
authors: Iqbal
authors: Daniela
authors: D
authors: Cantarella
authors: Riccardo
authors: R
authors: Taulli
authors: Paolo
authors: P
authors: Provero
authors: Ferdinando
authors: F
authors: Di Cunto
authors: Enzo
authors: E
authors: Medico
authors: Massimo
authors: M
authors: Negrini
authors: Wing C
authors: WC
authors: Chan
authors: Giorgio
authors: G
authors: Inghirami
authors: Roberto
authors: R
authors: Piva
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
references: Blood. 2013 Sep 19;122(12):2083-92
references: 23801630
references: J Clin Oncol. 2008 Sep 1;26(25):4124-30
references: 18626005
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2889-94
references: 18287052
references: N Engl J Med. 2010 Oct 28;363(18):1734-9
references: 20979473
references: Nat Med. 2005 Jun;11(6):623-9
references: 15895073
references: Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16228-33
references: 20805506
references: Science. 1994 Mar 4;263(5151):1281-4
references: 8122112
references: Sci Transl Med. 2012 Feb 8;4(120):120ra17
references: 22277784
references: Leukemia. 2011 Dec;25(12):1882-90
references: 21778999
references: Oncogene. 2007 Aug 16;26(38):5606-14
references: 17353907
references: Blood. 2011 Dec 22;118(26):6881-92
references: 22042699
references: Sci Transl Med. 2012 Feb 8;4(120):120ps2
references: 22323827
references: Oncogene. 2003 Aug 21;22(35):5399-407
references: 12934099
references: Hematol Oncol. 2009 Dec;27(4):161-70
references: 19358142
references: Clin Lymphoma Myeloma Leuk. 2011 Jun;11 Suppl 1:S87-90
references: 22035756
references: Mol Cancer. 2010 May 26;9:123
references: 20504344
references: Immunol Rev. 2013 May;253(1):158-66
references: 23550645
references: Mol Cancer Ther. 2012 Mar;11(3):670-9
references: 22203728
references: Nature. 2005 Jun 9;435(7043):828-33
references: 15944707
references: Blood. 2013 Jul 25;122(4):542-9
references: 23741012
references: PLoS One. 2008 May 21;3(5):e2236
references: 18493594
references: Cell. 2008 Mar 7;132(5):875-86
references: 18329372
references: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
references: 16461460
references: Cancer Res. 2011 May 15;71(10):3658-68
references: 21444672
references: Oncogene. 2004 Jul 15;23(32):5426-34
references: 15184887
references: Cancer Res. 2008 Jul 15;68(14):5540-5
references: 18632605
references: Cancer Res. 2004 May 1;64(9):3087-95
references: 15126345
references: Semin Oncol. 2009 Apr;36(2 Suppl 1):S27-35
references: 19393833
references: J Immunol. 2002 Jan 1;168(1):466-74
references: 11751994
references: Nature. 2012 Feb 15;482(7385):347-55
references: 22337054
references: Cancer Res. 2009 Nov 15;69(22):8611-9
references: 19887607
references: Nat Rev Cancer. 2008 Jan;8(1):11-23
references: 18097461
references: Clin Cancer Res. 2012 Jul 1;18(13):3592-602
references: 22553343
references: Nat Cell Biol. 2007 Jul;9(7):775-87
references: 17589498
references: Mol Cancer Res. 2013 Feb;11(2):122-32
references: 23239810
references: Cell. 2009 Jan 23;136(2):215-33
references: 19167326
references: Blood. 2011 Jun 16;117(24):6627-37
references: 21471522
references: Nat Rev Mol Cell Biol. 2010 Apr;11(4):252-63
references: 20216554
references: Chem Biol. 2006 Nov;13(11):1235-42
references: 17114005
references: J Clin Invest. 2006 Dec;116(12):3171-82
references: 17111047
references: Circ Res. 2009 May 22;104(10):1184-91
references: 19390056
references: J Clin Oncol. 2004 May 1;22(9):1682-8
references: 15117990
references: Oncogene. 2002 Feb 7;21(7):1038-47
references: 11850821
references: Cancer Res. 2006 Jul 1;66(13):6589-97
references: 16818631
references: J Clin Oncol. 2010 Mar 20;28(9):1583-90
references: 20159827
references: BMC Bioinformatics. 2010 Aug 09;11:419
references: 20696049
references: Front Oncol. 2012 May 11;2:41
references: 22649787
references: Leukemia. 2012 May;26(5):1064-72
references: 22116552
references: Nat Rev Genet. 2009 Oct;10(10):704-14
references: 19763153
references: Cancer Discov. 2012 Aug;2(8):694-705
references: 22719020