title: Oxidative stress associates with aggressiveness in lung large-cell carcinoma.
abstract: Oxidative stress is involved in many cancer-related processes; however, current therapeutics are unable to benefit from this approach. The lungs have a very exquisite redox environment that may contribute to the frequent and deadly nature of lung cancer. Very few studies specifically address lung large-cell carcinoma (LCC), even though this is one of the major subtypes. Using bioinformatic (in silico) tools, we demonstrated that a more aggressive lung LCC cell line (HOP-92) has an overall increase activity of the human antioxidant gene (HAG) network (P = 0.0046) when compared to the less aggressive cell line H-460. Gene set enrichment analysis (GSEA) showed that the expression of metallothioneins (MT), glutathione peroxidase 1 (GPx-1), and catalase (CAT) are responsible for this difference in gene signature. This was validated in vitro, where HOP-92 showed a pro-oxidative imbalance, presenting higher antioxidant enzymes (superoxide dismutase (SOD), CAT, and GPx) activities, lower reduced sulfhydryl groups and antioxidant potential, and higher lipoperoxidation and reactive species production. Also, HAG network is upregulated in lung LCC patients with worst outcome. Finally, the prognostic value of genes enriched in the most aggressive cell line was assessed in this cohort. Isoforms of metallothioneins are associated with bad prognosis, while the thioredoxin-interacting protein (TXNIP) is associated with good prognosis. Thus, redox metabolism can be an important aspect in lung LCC aggressiveness and a possible therapeutic target.
authors: Laboratory of Cellular Biochemistry, Department of Biochemistry, ICBS/UFRGS, 2600 Ramiro Barcelos St - lab. 24, 90035-003, Porto Alegre, RS, Brazil, llmrspa@gmail.com.
authors: Leonardo Lisboa
authors: LL
authors: da Motta
authors: Marco Antonio
authors: MA
authors: De Bastiani
authors: Fernanda
authors: F
authors: Stapenhorst
authors: Fábio
authors: F
authors: Klamt
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002374:Catalase / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics*; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D017382:Reactive Oxygen Species; C486715:TXNIP protein, human; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
references: BMC Med. 2011 May 23;9:62
references: 21605374
references: Mol Cancer Ther. 2012 Sep;11(9):2021-32
references: 22807579
references: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references: 16199517
references: Cancers (Basel). 2013 Jan 24;5(1):131-48
references: 24216701
references: Virchows Arch. 2014 Jan;464(1):61-8
references: 24221342
references: Acta Oncol. 2009;48(7):1054-61
references: 19308756
references: Lung Cancer. 2013 Dec;82(3):383-9
references: 24161719
references: Arch Pathol Lab Med. 2012 Oct;136(10):1190-3
references: 23020721
references: Sci Transl Med. 2014 Jan 29;6(221):221ra15
references: 24477002
references: Oncotarget. 2013 Dec;4(12):2577-90
references: 24342878
references: Front Biosci (Landmark Ed). 2009 Jan 01;14:4457-63
references: 19273363
references: BMC Cancer. 2011 May 23;11:191
references: 21605372
references: Cancer Res. 2004 Feb 15;64(4):1287-92
references: 14983878
references: Nat Rev Drug Discov. 2013 Dec;12(12):931-47
references: 24287781
references: Methods Enzymol. 1981;77:325-33
references: 7329310
references: Cancer Causes Control. 2000 Jan;11(1):49-58
references: 10680729
references: Mol Cancer. 2014 Mar 19;13:62
references: 24645981
references: J Cancer Res Clin Oncol. 2014 Mar;140(3):461-70
references: 24449404
references: Free Radic Biol Med. 2010 Mar 15;48(6):749-62
references: 20045723
references: Lung Cancer. 2009 Dec;66(3):298-304
references: 19324449
references: Cancer Lett. 2005 Sep 28;227(2):133-9
references: 16112416
references: Bioinformatics. 2009 Jun 1;25(11):1468-9
references: 19369498
references: Mol Carcinog. 2004 Feb;39(2):103-13
references: 14750215
references: FEBS Lett. 1994 Mar 14;341(1):59-64
references: 8137923
references: Anal Biochem. 2009 Feb 1;385(1):107-14
references: 19027710
references: J Clin Oncol. 2013 Mar 10;31(8):992-1001
references: 23401443
references: Adv Drug Deliv Rev. 2009 Apr 28;61(4):319-26
references: 19385054
references: Appl Immunohistochem Mol Morphol. 2009 Oct;17(5):383-92
references: 19444077
references: Mutat Res. 2003 Dec 10;533(1-2):201-9
references: 14643421
references: Breast Cancer Res. 2010;12(3):R44
references: 20584310
references: Free Radic Biol Med. 2009 Nov 1;47(9):1282-93
references: 19486941
references: J Thorac Oncol. 2009 Feb;4(2):172-8
references: 19179892
references: Eur J Pharmacol. 2006 Mar 8;533(1-3):222-39
references: 16500642
references: Eur Respir J. 2007 Feb;29(2):273-8
references: 17005588
references: Anticancer Res. 2003 May-Jun;23(3B):2425-33
references: 12894524
references: Histol Histopathol. 1996 Oct;11(4):851-60
references: 8930626
references: Nucleic Acids Res. 2007;35(6):1859-67
references: 17332015
references: J Biol Chem. 1972 May 25;247(10):3170-5
references: 4623845
references: Int J Environ Res Public Health. 2013 Aug 27;10(9):3886-907
references: 23985773
references: Int J Radiat Oncol Biol Phys. 2012 Oct 1;84(2):492-9
references: 22381900
references: Cancer Lett. 2011 Jun 1;305(1):58-68
references: 21411221
references: Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1706-11
references: 8970359
references: Lung Cancer. 2008 May;60(2):277-84
references: 18061304
references: Nat Rev Clin Oncol. 2014 Mar;11(3):167-76
references: 24492837
references: Cancer Res. 1997 Jan 1;57(1):152-5
references: 8988057
references: Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2089-98
references: 20798378
references: World J Gastroenterol. 2012 Oct 21;18(39):5581-8
references: 23112551
references: Nat Protoc. 2006;1(3):1112-6
references: 17406391
references: Carcinogenesis. 2011 Oct;32(10):1459-66
references: 21771725
references: CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29
references: 24399786
references: Int J Cancer. 2002 Jan 1;97(1):34-41
references: 11774241
references: Respirology. 2008 Jan;13(1):112-6
references: 18197920
references: Cancer Res. 2007 Nov 1;67(21):10260-7
references: 17974967
references: J Biol Chem. 2005 Jun 3;280(22):21346-52
references: 15799967
references: Cancer Metastasis Rev. 2010 Jun;29(2):351-78
references: 20386957