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Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma

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Tumor Biology

Abstract

In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54 %, p = 0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19 % of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients’ shorter survival time.

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References

  1. Demuth T, Berens ME. Molecular mechanisms of glioma cell migration and invasion. J Neurooncol. 2004;70:217–28.

    Article  PubMed  Google Scholar 

  2. Kotliarov Y, Kotliarova S, Charong N, Li A, Walling J, Aquilanti E, et al. Correlation analysis between single-nucleotide polymorphism and expression arrays in gliomas identifies potentially relevant target genes. Cancer Res. 2009;69:1596–603.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Shai R, Shi T, Kremen TJ, Horvath S, Liau LM, Cloughesy TF, et al. Gene expression profiling identifies molecular subtypes of gliomas. Oncogene. 2003;22:4918–23.

    Article  PubMed  CAS  Google Scholar 

  4. Ohgaki H. Genetic pathways to glioblastomas. Neuropathology. 2005;25:1–7.

    Article  PubMed  Google Scholar 

  5. Li A, Bozdag S, Kotliarov Y, Fine HA. GliomaPredict: a clinically useful tool for assigning glioma patients to specific molecular subtypes. BMC Med Inform Decis Mak. 2010;10:38. doi:10.1186/1472-6947-10-38.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumors of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ware ML, Berger MS, Binder DK. Molecular biology of glioma tumorigenesis. Histol Histopathol. 2003;18:207–16.

    PubMed  CAS  Google Scholar 

  8. Reifenberger G, Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol Med. 2004;82:656–70.

    Article  PubMed  CAS  Google Scholar 

  9. Huse JT, Holland EC. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 2010;10:319–31.

    Article  PubMed  CAS  Google Scholar 

  10. Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97:880–7.

    Article  PubMed  CAS  Google Scholar 

  11. Raizer JJ. HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. J Neurooncol. 2005;74:77–86.

    Article  PubMed  CAS  Google Scholar 

  12. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci U S A. 1968;61:748–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. De Matteis F, Dawson SJ, Pons N, Pipino S. Bilirubin and uroporphyrinogen oxidation by induced cytochrome P4501A and cytochrome P4502B. Role of polyhalogenated biphenyls of different configuration. Biochem Pharmacol. 2002;63:615–24.

    Article  PubMed  Google Scholar 

  14. Jozkowicz A, Was H, Dulak J. Heme oxygenase-1 in tumors: is it a false friend? Antioxid Redox Signal. 2007;9:2099–117.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med. 2000;6:422–8.

    Article  PubMed  CAS  Google Scholar 

  16. Snyder SH, Barañano DE. Heme oxygenase: a font of multiple messengers. Neuropsychopharmacology. 2001;25:294–8.

    Article  PubMed  CAS  Google Scholar 

  17. Maines MD, Gibbs PE. 30 some years of heme oxygenase: from a “molecular wrecking ball” to a “mesmerizing” trigger of cellular events. Biochem Biophys Res Commun. 2005;338:568–77.

    Article  PubMed  CAS  Google Scholar 

  18. Was H, Dulak J, Jozkowickz A. Heme oxygenase-1 in tumor biology and therapy. Curr Drug Targets. 2010;11:1551–70.

    Article  PubMed  CAS  Google Scholar 

  19. Dwyer BE, Nishimura RN, Lu SY. Differential expression of heme oxygenase-1 in cultured cortical neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress. Brain Res Mol Brain Res. 1995;30:37–47.

    Article  PubMed  CAS  Google Scholar 

  20. Schipper HM. Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med. 2004;37:1995–2011.

    Article  PubMed  CAS  Google Scholar 

  21. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  22. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  PubMed  CAS  Google Scholar 

  23. Gandini NA, Fermento ME, Salomón DG, Blasco J, Patel V, Gutkind JS, et al. Nuclear localization of heme oxygenase-1 is associated with tumor progression of head and neck squamous cell carcinomas. Exp Mol Pathol. 2012;93:237–45.

    Article  PubMed  CAS  Google Scholar 

  24. Degese MS, Mendizabal JE, Gandini NA, Gutkind JS, Molinolo A, Hewitt SM, et al. Expression of heme oxygenase-1 in non-small cell lung cancer (NSCLC) and its correlation with clinical data. Lung Cancer. 2012;77:168–75.

    Article  PubMed  Google Scholar 

  25. Hara E, Takahashi K, Tominaga T, Kumabe T, Kayama T, Suzuki H, et al. Expression of heme oxygenase and inducible nitric oxide synthase mRNA in human brain tumors. Biochem Biophys Res Commun. 1996;224:153–8.

    Article  PubMed  CAS  Google Scholar 

  26. Deininger MH, Meyermann R, Trautmann K, Duffner F, Grote EH, Wickboldt J, et al. Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulates during oligodendroglioma progression. Brain Res. 2000;882:1–8.

    Article  PubMed  CAS  Google Scholar 

  27. El Andaloussi A, Lesniak MS. CD4+CD25+FoxP3+ T-cell infiltration and heme oxygenase-1 expression correlate with tumor grade in human gliomas. J Neurooncol. 2007;83:145–52.

    Article  PubMed  CAS  Google Scholar 

  28. Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res. 1999;5:1107–13.

    PubMed  CAS  Google Scholar 

  29. Lin Q, Weis S, Yang G, Weng YH, Helston R, Rish K, et al. Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress. J Biol Chem. 2007;282:20621–33.

    Article  PubMed  CAS  Google Scholar 

  30. Sacca P, Meiss R, Casas G, Mazza O, Calvo JC, Navone N, et al. Nuclear translocation of haeme oxygenase-1 is associated to prostate cancer. Br J Cancer. 2007;97:1683–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Tibullo D, Barbagallo I, Giallongo C, La Cava P, Parrinello N, Vanella L, et al. Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells. Curr Pharm Des. 2013;19:2765–70.

    Article  PubMed  CAS  Google Scholar 

  32. Li Volti G, Ientile R, Abraham NG, Vanella A, Cannavò G, Mazza F, et al. Immunocytochemical localization and expression of heme oxygenase-1 in primary astroglial cell culture during differentiation: effect of glutamate. Biochem Biophys Res Commun. 2004;315:517–24.

    Article  PubMed  CAS  Google Scholar 

  33. Madhavan S, Zenklusen JC, Kotliarov Y, Sahni H, Fine HA, Buetow K. Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol Cancer Res. 2009;7:157–67.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Greene FL. The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg. 2002;87:13–5.

    PubMed  Google Scholar 

  35. Facchinetti MM, Gandini NA, Fermento ME, Sterin-Speziale NB, Ji Y, Vyomesh Patel J, et al. The expression of sphingosine kinase-1 in head and neck carcinoma. Cells Tissues Organs. 2010;192:314–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zlobec I, Steele R, Terracciano L, Jass JR, Lugli A. Selecting immunohistochemical cut-off scores for novel biomarkers of progression and survival in colorectal cancer. J Clin Pathol. 2007;60(10):1112–6.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Petit V, Boyer B, Lentz D, Turner CE, Thiery JP, Valles AM. Phosphorylation of tyrosine residues 31 and 118 on paxillin regulates cell migration through an association with CRK in NBT-II cells. J Cell Biol. 2000;148:957–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Schacter BA, Kurz P. Alterations in hepatic and splenic microsomal electron transport system components, drug metabolism, heme oxygenase activity, and cytochrome P-450 turnover in Murphy–Sturm lymphosarcoma-bearing rats. Cancer Res. 1982;42:3557–64.

    PubMed  CAS  Google Scholar 

  39. Maines MD, Abrahamsson PA. Expression of heme oxygenase-1 (HSP32) in human prostate: normal, hyperplastic, and tumor tissue distribution. Urology. 1996;47:727–33.

    Article  PubMed  CAS  Google Scholar 

  40. Goodman AI, Choudhury M, daSilva JL, Schwartzman ML, Abraham NG. Overexpression of the heme oxygenase gene in renal cell carcinoma. Proc Soc for Exp Biol Med. 1997;214:54–61.

    Article  CAS  Google Scholar 

  41. Doi K, Akaike T, Fujii S, Tanaka S, Ikebe N, Beppu T, et al. Induction of haem oxygenase-1 nitric oxide and ischaemia in experimental solid tumors and implications for tumor growth. Br J Cancer. 1999;80:1945–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Torisu-Itakura H, Furue M, Kuwano M, Ono M. Co-expression of thymidine phosphorylase and heme oxygenase-1 in macrophages in human malignant vertical growth melanomas. Jpn J Cancer Res. 2000;91:906–10.

    Article  PubMed  CAS  Google Scholar 

  43. McAllister SC, Hansen SG, Ruhl RA, Raggo CM, DeFilippis VR, Greenspan D, et al. Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells. Blood. 2004;103:3465–73.

    Article  PubMed  CAS  Google Scholar 

  44. Berberat PO, Dambrauskas Z, Gulbinas A, Giese T, Giese N, Künzli B, et al. Inhibition of heme oxygenase-1 increases responsiveness of pancreatic cancer cells to anticancer treatment. Clin Cancer Res. 2005;11:3790–8.

    Article  PubMed  CAS  Google Scholar 

  45. Mayerhofer M, Florian S, Krauth MT, Aichberger KJ, Bilban M, Marculescu R, et al. Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia. Cancer Res. 2004;64:3148–54.

    Article  PubMed  CAS  Google Scholar 

  46. Chang KW, Lee TC, Yeh WI, Chung MY, Liu CJ, Chi LY, et al. Polymorphism in heme oxygenase-1 (HO-1) promoter is related to the risk of oral squamous cell carcinoma occurring on male areca chewers. Br J Cancer. 2004;91:1551–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lee J, Lee SK, Lee BU, Lee HJ, Cho NP, Yoon JH, et al. Upregulation of heme oxygenase-1 in oral epithelial dysplasias. Int J Oral Maxillofac Surg. 2008;37:287–92.

    Article  PubMed  CAS  Google Scholar 

  48. Lee SS, Yang SF, Tsai CH, Chou MC, Chou MY, Chang YC. Upregulation of heme oxygenase-1 expression in areca-quid-chewing-associated oral squamous cell carcinoma. J Formos Med Assoc. 2008;107:355–63.

    Article  PubMed  CAS  Google Scholar 

  49. Liu Y, Liang Y, Zheng T, Yang G, Zhang X, Sun Z, et al. Inhibition of heme oxygenase-1 enhances anti-cancer effects of arsenic trioxide on glioma cells. J Neurooncol. 2011;104:449–58.

    Article  PubMed  CAS  Google Scholar 

  50. Chen CH, Chang YJ, Ku MS, Chung KT, Yang JT. Enhancement of temozolomide-induced apoptosis by valproic acid in human glioma cell lines through redox regulation. J Mol Med (Berl). 2011;89:303–15.

    Article  PubMed  CAS  Google Scholar 

  51. Long J, Manchandia T, Ban K, Gao S, Miller C, Chandra J. Adaphostin cytoxicity in glioblastoma cells is ROS-dependent and is accompanied by upregulation of heme oxygenase-1. Cancer Chemother Pharmacol. 2007;59:527–635.

    Article  PubMed  CAS  Google Scholar 

  52. Asharani PV, Hande MP, Valiyaveettil S. Anti-proliferative activity of silver nanoparticles. BMC Cell Biol. 2009;10:65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Gueron G, De Siervi A, Ferrando M, Salierno M, De Luca P, Elguero B, et al. Critical role of endogenous heme oxygenase 1 as a tuner of the invasive potential of prostate cancer cells. Mol Cancer Res. 2009;7:1745–55. doi:10.1158/1541-7786.MCR-08-0325.

    Article  PubMed  CAS  Google Scholar 

  54. Ferrando M, Gueron G, Elguero B, Giudice J, Salles A, Leskow FC, et al. Heme oxygenase 1 (HO-1) challenges the angiogenic switch in prostate cancer. Angiogenesis. 2011;14(4):467–79.

    Article  PubMed  CAS  Google Scholar 

  55. Miyake M, Fujimoto K, Anai S, Ohnishi S, Nakai Y, Inoue T, et al. Clinical significance of heme oxygenase-1 expression in non-muscle-invasive bladder cancer. Urol Int. 2010;85:355–63. doi:10.1159/000317785.

    Article  PubMed  CAS  Google Scholar 

  56. Yim MS, Ha YS, Kim IY, Yun SJ, Choi YH, Kim WJ. HMOX1 is an important prognostic indicator of nonmuscle invasive bladder cancer recurrence and progression. J Urol. 2011;185:701–5.

    Article  PubMed  CAS  Google Scholar 

  57. Tsai JR, Wang HM, Liu PL, Chen YH, Yang MC, Chou SH, et al. High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patients. Cell Oncol (Dordr). 2012;35:461–71.

    Article  PubMed  CAS  Google Scholar 

  58. Yanagawa T, Omura K, Harada H, Nakaso K, Iwasa S, Koyama Y, et al. Heme oxygenase-1 expression predicts cervical lymph node metastasis of tongue squamous cell carcinomas. Oral Oncol. 2004;40:21–7.

    Article  PubMed  CAS  Google Scholar 

  59. Becker JC, Fukui H, Imai Y, Sekikawa A, Kimura T, Yamagishi H, et al. Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand J Gastroenterol. 2007;42:852–8.

    Article  PubMed  CAS  Google Scholar 

  60. Li Y, Su J, DingZhang X, Zhang J, Yoshimoto M, Liu S, et al. PTEN deletion and heme oxygenase-1 overexpression cooperate in prostate cancer progression and are associated with adverse clinical outcome. J Pathol. 2011;224:90–100. doi:10.1002/path.2855.

    Article  PubMed  CAS  Google Scholar 

  61. Al-Owais MM, Scragg JL, Dallas ML, Boycott HE, Warburton P, Chakrabarty A, et al. Carbon monoxide mediates the anti-apoptotic effects of heme oxygenase-1 in medulloblastoma DAOY cells via K+ channel inhibition. J Biol Chem. 2012;287:24754–64. doi:10.1074/jbc.M112.357012.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Lu TH, Pepe JA, Gildemeister OS, Tyrrell RM, Bonkovsky HL. Regulation of expression of the human heme oxygenase-1 gene in transfected chick embryo liver cell cultures. Biochim Biophys Acta. 1997;1352:293–302.

    Article  PubMed  CAS  Google Scholar 

  63. Pan HC, Yang CN, Hung YW, Lee WJ, Tien HR, Shen CC, et al. Reciprocal modulation of C/EBPα and C/EBPβ by IL-13 in activated microglia prevents neuronal death. Eur J Immunol. 2013. doi:10.1002/eji.201343301.

    Google Scholar 

  64. Birrane G, Li H, Yang S, Tachado SD, Seng S. Cigarette smoke induces nuclear translocation of heme oxygenase 1 (HO-1) in prostate cancer cells: nuclear HO-1 promotes vascular endothelial growth factor secretion. Int J Oncol. 2013;42:1919–28. doi:10.3892/ijo.2013.1910.

    PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from CONICET, ANPCyT and from the Technical Secretary of the Universidad Nacional del Sur. Gandini NA, Fermento ME, Andrés NC, Obiol DJ, and Salomón DG are recipients of a fellowship from CONICET.

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Authors and Affiliations

  1. Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB-CONICET), Camino La Carrindanga Km 7, 8000, Bahía Blanca, Argentina

    Norberto A. Gandini, María E. Fermento, Débora G. Salomón, Diego J. Obiol, Nancy C. Andrés, María M. Facchinetti & Alejandro C. Curino

  2. The Cancer Genome Atlas Program Office, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Jean C. Zenklusen

  3. Servicio de Patología del Hospital Interzonal de Agudos Dr. José Penna, Bahía Blanca, Argentina

    Julián Arevalo & Jorge Blasco

  4. Laboratorios IACA, Bahía Blanca, Argentina

    Alejandro López Romero

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  1. Norberto A. Gandini
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  2. María E. Fermento
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  3. Débora G. Salomón
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  4. Diego J. Obiol
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  5. Nancy C. Andrés
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  6. Jean C. Zenklusen
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  7. Julián Arevalo
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  8. Jorge Blasco
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  9. Alejandro López Romero
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  10. María M. Facchinetti
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  11. Alejandro C. Curino
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Corresponding author

Correspondence to Alejandro C. Curino.

Electronic supplementary material

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Online Resource 1

Selected TMA cases showing different HO-1 expression levels as determined by the IRS. a Non-malignant tissue (IRS = 0). b ASTRO II (IRS = 0). c ASTRO II (IRS = 2). d ASTRO III (IRS = 4). e ASTRO II (IRS = 6). f ASTRO IV (IRS = 9). Original magnification, ×400 (PDF 399 kb)

Online Resource 2

IRS of the studied population (PDF 22 kb)

Online Resource 3

Survival curves and Cox regression analysis of the relationship between survival and the variables HO-1 mRNA levels, age, and grade. HR hazard ratio (PDF 65 kb)

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Gandini, N.A., Fermento, M.E., Salomón, D.G. et al. Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma. Tumor Biol. 35, 2803–2815 (2014). https://doi.org/10.1007/s13277-013-1373-z

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