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Tumor Biology

, Volume 36, Issue 6, pp 4681–4688 | Cite as

Oxidative stress associates with aggressiveness in lung large-cell carcinoma

  • Leonardo Lisboa da Motta
  • Marco Antonio De Bastiani
  • Fernanda Stapenhorst
  • Fábio Klamt
Research Article

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.

Keywords

Tumor progression Catalase Lung cancer Hydrogen peroxide H661 

Notes

Acknowledgments

We thank Dr. Karin Purshouse for revising the manuscript and the Brazilians funds—PPSUS FAPERGS/MS/CNPq/SESRS/PPSUS (1121-2551/13-8), MCT/CNPq Universal (470306/2011-4), PRONEX/FAPERGS (1000274), PRONEM/FAPERGS (11/2032-5), PqG/FAPERGS (2414-2551/12-8), and MCT/CNPq INCT-TM (573671/2008-7)—for financial support.

Conflicts of interest

None

Supplementary material

13277_2015_3116_Fig4_ESM.gif (50 kb)
Figure S1

Landscape analysis comparing the expression of Human Antioxidant Gene (HAG) network in human lung large cell carcinoma (LCC) cell lines H-460 and H661, using two datasets, GSE4824 (a) and GSE14925 (b), generated with ViaComplex® V1.0. Color gradient (Z-axis) represents the relative functional state mapped onto graph according to the data input from the lung LCC H-460-a vs. H-661-b, where z=a/(a+b). P value refers to Bootstrap analysis comparing cell lines. (GIF 49 kb)

13277_2015_3116_MOESM1_ESM.tif (407 kb)
High resolution image (TIFF 406 kb)
13277_2015_3116_Fig5_ESM.gif (77 kb)
Figure S2

Redox state influences growth of lung large cell carcinoma cell lines. Treatment with exogenous catalase (125–1000 U/mL) for 72 h cause dose-dependent inhibition in cell proliferation of lung LCC cell lines (a). CAT washout after 48 h of incubation allowed cells to return to its original proliferation rate (b). Dose response curve against H2O2 in lung LCC cell lines. Sub-lethal doses (<40 μM) of H2O2 stimulate cell growth of HOP-92 (c). Data is mean ± S.E.M. of at least three independent experiments (n = 3), performed in triplicate. * P < 0.05 (Student’s t-test compared to untreated group). (GIF 76 kb)

13277_2015_3116_MOESM2_ESM.tif (255 kb)
High resolution image (TIFF 255 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Leonardo Lisboa da Motta
    • 1
    • 2
  • Marco Antonio De Bastiani
    • 1
    • 2
  • Fernanda Stapenhorst
    • 1
    • 2
  • Fábio Klamt
    • 1
    • 2
  1. 1.Laboratory of Cellular Biochemistry, Department of BiochemistryICBS/UFRGSPorto AlegreBrazil
  2. 2.National Institutes of Science and Technology–Translational Medicine (INCT-TM)Porto AlegreBrazil

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