title: ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non-small cell lung cancer.
abstract: OBJECTIVE
  The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly downregulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis.
  
  
  METHODS
  Lung adenocarcinomas (n = 80) and normal lung tissues (n = 30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was conducted to determine ETS2 protein expression in non-small cell lung cancer (NSCLC) histologic tissue specimens (n = 201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log-rank and Kaplan-Meier tests. RNA interference and overexpression strategies were used to assess the effects of ETS2 expression on the transcriptome and on various malignant phenotypes.
  
  
  RESULTS
  ETS2 expression was significantly reduced in lung adenocarcinomas compared with normal lung (P < 0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (P = 0.009, HR = 1.89) and adenocarcinoma (P = 0.03, HR = 1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration, and invasion (P < 0.05), and microarray and pathways analysis revealed significant (P < 0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (P < 0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration, and invasion.
  
  
  CONCLUSIONS
  Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene.
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Mohamed
authors: M
authors: Kabbout
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Melinda M
authors: MM
authors: Garcia
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Junya
authors: J
authors: Fujimoto
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Diane D
authors: DD
authors: Liu
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Denise
authors: D
authors: Woods
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Chi-Wan
authors: CW
authors: Chow
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Gabriela
authors: G
authors: Mendoza
authors: Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Amin A
authors: AA
authors: Momin
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Brian P
authors: BP
authors: James
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Luisa
authors: L
authors: Solis
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Carmen
authors: C
authors: Behrens
authors: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: J Jack
authors: JJ
authors: Lee
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Ignacio I
authors: II
authors: Wistuba
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Humam
authors: H
authors: Kadara
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D000090063:Proto-Oncogene Mas; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050787:Proto-Oncogene Protein c-ets-2; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
references: Biochem J. 2008 Jun 1;412(2):287-98
references: 18321244
references: Nat Rev Cancer. 2007 Jun;7(6):415-28
references: 17508028
references: Br J Cancer. 2011 Sep 6;105(6):814-23
references: 21847116
references: Science. 1991 Feb 15;251(4995):802-4
references: 1846706
references: Cancer Res. 2003 Nov 1;63(21):7345-55
references: 14612533
references: Biochem Biophys Res Commun. 2003 Aug 22;308(2):270-5
references: 12901864
references: Stem Cells. 2006 Jul;24(7):1707-18
references: 16574750
references: PLoS One. 2008 Feb 20;3(2):e1651
references: 18297132
references: Stem Cells. 2011 Mar;29(3):430-9
references: 21425406
references: Clin Cancer Res. 2011 Apr 15;17(8):2434-43
references: 21257719
references: Oncogene. 2008 May 8;27(21):3021-31
references: 18059336
references: Oncogene. 2011 Aug 18;30(33):3625-35
references: 21423210
references: Cancer Res. 1999 Sep 1;59(17):4242-6
references: 10485465
references: J Biol Chem. 2010 Aug 20;285(34):26417-30
references: 20554528
references: J Cell Sci. 2013 Jun 1;126(Pt 11):2381-91
references: 23549785
references: Carcinogenesis. 2012 Apr;33(4):760-9
references: 22298639
references: Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37
references: 11715049
references: Exp Cell Res. 2003 Oct 15;290(1):132-43
references: 14516794
references: J Cell Biochem. 2004 Apr 1;91(5):896-903
references: 15034925
references: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references: 22237781
references: Oncogene. 1998 Dec 3;17(22):2883-8
references: 9879994
references: Mol Cell Biol. 1996 Feb;16(2):538-47
references: 8552081
references: Cancer Res. 2010 Feb 15;70(4):1323-33
references: 20145133
references: J Biol Chem. 1998 Jul 24;273(30):18871-80
references: 9668063
references: Genes Dev. 1998 May 1;12(9):1315-26
references: 9573048
references: Cancer Res. 2003 Aug 1;63(15):4626-31
references: 12907642
references: Blood. 2009 Jul 30;114(5):1123-30
references: 19411629
references: Trends Mol Med. 2010 Jan;16(1):37-45
references: 20031486
references: Nature. 2008 Jan 3;451(7174):73-5
references: 18172498
references: Cancer Res. 2003 Sep 1;63(17):5344-51
references: 14500366
references: J Biol Chem. 2008 Aug 29;283(35):23567-80
references: 18586674
references: Cancer Inform. 2007 Feb 04;3:11-7
references: 19455231
references: Am J Pathol. 2009 Nov;175(5):2207-16
references: 19834061
references: J Thorac Oncol. 2012 Jan;7(1):20-33
references: 22011669
references: Clin Cancer Res. 2001 Jun;7(6):1669-75
references: 11410505
references: Cancer Cell. 2010 Jan 19;17(1):77-88
references: 20129249
references: Oncol Rep. 2002 Jul-Aug;9(4):853-7
references: 12066221
references: Cancer Res. 2005 Dec 15;65(24):11572-80
references: 16357167
references: J Thorac Oncol. 2012 Feb;7(2):331-9
references: 22198430
references: Leukemia. 2008 Mar;22(3):521-9
references: 18094719
references: N Engl J Med. 2008 Sep 25;359(13):1367-80
references: 18815398
references: Am J Respir Crit Care Med. 2005 Sep 15;172(6):729-37
references: 15976377
references: Eur J Cancer. 2005 Nov;41(16):2462-78
references: 16213704
references: Br J Cancer. 2005 Sep 19;93(6):719-29
references: 16222316
references: Cancer Res. 2001 Mar 1;61(5):2267-75
references: 11280797
references: Sci Transl Med. 2010 Apr 7;2(26):26ra25
references: 20375364
references: Nat Rev Drug Discov. 2008 Jun;7(6):504-16
references: 18511928
references: Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
references: 14685170
references: J Clin Invest. 2007 Apr;117(4):978-88
references: 17347682