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PMID: 17180667 Published · ppublish English Journal Article Review

Hypoxia-induced genetic instability--a calculated mechanism underlying tumor progression.

Journal of molecular medicine (Berlin, Germany) ·Vol. 85 ·No. 2 ·2007-02-00 ·Pages 139-48

Huang LE, Bindra RS, Glazer PM, Harris AL

Abstract

The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability-the hallmark of human cancers-is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a result of expansion and progression-two complementary aspects that collaborate with the tumor microenvironment-hypoxia in particular, on genetic alterations through the induction of genetic instability. In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and discuss the biomedical implications in cancer biology and treatment.

MeSH Terms
DNA Repair/physiology Disease Progression Genomic Instability Humans Hypoxia/complications Neoplasms/etiology,pathology
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Huang L Eric
Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. eric.huang@hsc.utah.edu
Bindra Ranjit S
Glazer Peter M
Harris Adrian L
References (85)
85 references, click to expand
  1. Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma.
    FASEB J. 2005 Sep;19(11):1396-406 PMID: 16126907
  2. ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation.
    J Biol Chem. 2003 Apr 4;278(14 ):12207-13 PMID: 12519769
  3. In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays.
    Cancer Res. 1994 Jun 15;54(12):3173-8 PMID: 8205536
  4. A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs.
    Mol Cell. 1998 Aug;2(2):259-65 PMID: 9734364
  5. An essential role for p300/CBP in the cellular response to hypoxia.
    Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):12969-73 PMID: 8917528
  6. Association of DNA-dependent protein kinase with hypoxia inducible factor-1 and its implication in resistance to anticancer drugs in hypoxic tumor cells.
    Exp Mol Med. 2004 Jun 30;36(3):233-42 PMID: 15272235
  7. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
    Nature. 1999 May 20;399(6733):271-5 PMID: 10353251
  8. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
    J Biol Chem. 1996 Dec 20;271(51):32529-37 PMID: 8955077
  9. RORA, a large common fragile site gene, is involved in cellular stress response.
    Oncogene. 2006 May 11;25(20):2901-8 PMID: 16462772
  10. Microenvironmental influences on mutagenesis in mammary epithelial cells.
    Int J Cancer. 2005 Sep 20;116(5):679-85 PMID: 15849743
  11. Ischemia-induced K-ras mutations in human colorectal cancer cells: role of microenvironmental regulation of MSH2 expression.
    Cancer Res. 2005 Sep 15;65(18):8134-41 PMID: 16166287
  12. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation.
    Science. 2001 Apr 20;292(5516):468-72 PMID: 11292861
  13. Cancer susceptibility and the functions of BRCA1 and BRCA2.
    Cell. 2002 Jan 25;108(2):171-82 PMID: 11832208
  14. The E2F transcriptional network: old acquaintances with new faces.
    Oncogene. 2005 Apr 18;24(17):2810-26 PMID: 15838517
  15. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil.
    Br J Surg. 1991 Jun;78(6):651-5 PMID: 2070226
  16. Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines.
    J Natl Cancer Inst. 1990 Apr 18;82(8):684-92 PMID: 1969493
  17. Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene.
    Cancer Chemother Pharmacol. 2006 Dec;58(6):776-84 PMID: 16532342
  18. Common fragile sites.
    Cytogenet Genome Res. 2003;100(1-4):92-100 PMID: 14526169
  19. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.
    Cell Metab. 2006 Mar;3(3):177-85 PMID: 16517405
  20. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs.
    Cancer Res. 2005 Dec 15;65(24):11597-604 PMID: 16357170
  21. A conserved family of prolyl-4-hydroxylases that modify HIF.
    Science. 2001 Nov 9;294(5545):1337-40 PMID: 11598268
  22. Genetic instability induced by the tumor microenvironment.
    Cancer Res. 1996 Dec 15;56(24):5754-7 PMID: 8971187
  23. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.
    Science. 2001 Apr 20;292(5516):464-8 PMID: 11292862
  24. Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation.
    Cancer Res. 2004 Sep 15;64(18):6556-62 PMID: 15374968
  25. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
    Mol Cell Biol. 2004 Oct;24(19):8504-18 PMID: 15367671
  26. Human rad21 gene, hHR21(SP), is downregulated by hypoxia in human tumor cells.
    Biochem Biophys Res Commun. 2001 Mar;281(5):1106-12 PMID: 11243849
  27. The hallmarks of cancer.
    Cell. 2000 Jan 7;100(1):57-70 PMID: 10647931
  28. Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.
    Proc Natl Acad Sci U S A. 1988 Dec;85(24):9533-7 PMID: 3200838
  29. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption.
    Cell Metab. 2006 Mar;3(3):187-97 PMID: 16517406
  30. The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression.
    EMBO J. 2006 Oct 18;25(20):4784-94 PMID: 17024177
  31. Mammalian DNA mismatch repair.
    Annu Rev Genet. 1999;33:533-64 PMID: 10690417
  32. Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures.
    Cancer Res. 2001 Jan 15;61(2):428-32 PMID: 11212225
  33. Hypoxia-inducible factor and its biomedical relevance.
    J Biol Chem. 2003 May 30;278(22):19575-8 PMID: 12639949
  34. Dynamic balancing of the dual nature of HIF-1alpha for cell survival.
    Cell Cycle. 2004 Jul;3(7):853-4 PMID: 15190211
  35. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours.
    Nature. 1996 Jan 4;379(6560):88-91 PMID: 8538748
  36. The E2F family: specific functions and overlapping interests.
    EMBO J. 2004 Dec 8;23(24):4709-16 PMID: 15538380
  37. Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair.
    Mol Cell Biol. 2004 Jan;24(2):708-18 PMID: 14701743
  38. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy.
    Oncogene. 2003 May 22;22(21):3213-20 PMID: 12761491
  39. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation.
    Cell. 2001 Oct 5;107(1):43-54 PMID: 11595184
  40. The Mre11 complex: at the crossroads of dna repair and checkpoint signalling.
    Nat Rev Mol Cell Biol. 2002 May;3(5):317-27 PMID: 11988766
  41. Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes.
    J Virol. 2001 Aug;75(15):6737-47 PMID: 11435552
  42. Detection of S-phase overreplication following chronic hypoxia using a monoclonal anti-BrdUrd.
    Int J Radiat Oncol Biol Phys. 1985 Oct;11(10 ):1817-22 PMID: 4044344
  43. HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression.
    Mol Cell. 2005 Mar 18;17(6):793-803 PMID: 15780936
  44. Genetic instability: the dark side of the hypoxic response.
    Cell Cycle. 2005 Jul;4(7):881-2 PMID: 15970707
  45. HIF-1 and tumour radiosensitivity.
    Br J Cancer. 2006 Jul 3;95(1):1-5 PMID: 16735998
  46. Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1.
    Radiother Oncol. 2005 Apr;75(1):89-98 PMID: 15878106
  47. Hypoxia links ATR and p53 through replication arrest.
    Mol Cell Biol. 2002 Mar;22(6):1834-43 PMID: 11865061
  48. Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit.
    J Biol Chem. 1996 Dec 13;271(50):32253-9 PMID: 8943284
  49. E2Fs link the control of G1/S and G2/M transcription.
    EMBO J. 2004 Nov 24;23(23):4615-26 PMID: 15510213
  50. Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit.
    J Biol Chem. 1997 Apr 25;272(17 ):11205-14 PMID: 9111021
  51. Emerging roles for E2F: beyond the G1/S transition and DNA replication.
    Cancer Cell. 2003 Apr;3(4):311-6 PMID: 12726857
  52. Rules for making human tumor cells.
    N Engl J Med. 2002 Nov 14;347(20):1593-603 PMID: 12432047
  53. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.
    J Natl Cancer Inst. 2001 Feb 21;93(4):266-76 PMID: 11181773
  54. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  55. Hypoxia--a key regulatory factor in tumour growth.
    Nat Rev Cancer. 2002 Jan;2(1):38-47 PMID: 11902584
  56. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis.
    Mutat Res. 2005 Jan 6;569(1-2):75-85 PMID: 15603753
  57. HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98 (17 ):9630-5 PMID: 11504942
  58. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules.
    Cancer Cell. 2004 May;5(5):429-41 PMID: 15144951
  59. Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest.
    Mutat Res. 2003 Nov 27;532(1-2):205-13 PMID: 14643437
  60. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4 PMID: 7539918
  61. Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells.
    Radiother Oncol. 2005 Aug;76(2):168-76 PMID: 16026872
  62. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein.
    Nat Cell Biol. 2000 Jul;2(7):423-7 PMID: 10878807
  63. Mutagenesis induced by the tumor microenvironment.
    Mutat Res. 1998 May 25;400(1-2):439-46 PMID: 9685702
  64. Cancer-susceptibility genes. Gatekeepers and caretakers.
    Nature. 1997 Apr 24;386(6627):761, 763 PMID: 9126728
  65. Alterations in DNA repair gene expression under hypoxia: elucidating the mechanisms of hypoxia-induced genetic instability.
    Ann N Y Acad Sci. 2005 Nov;1059:184-95 PMID: 16382054
  66. Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells.
    Proc Natl Acad Sci U S A. 1986 Aug;83(16):5978-82 PMID: 3461470
  67. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein.
    EMBO J. 2000 Aug 15;19(16):4298-309 PMID: 10944113
  68. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia.
    EMBO J. 2003 Aug 15;22(16):4082-90 PMID: 12912907
  69. Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation.
    Cancer Res. 2002 May 15;62(10 ):2957-61 PMID: 12019178
  70. DNA damage and repair.
    Nature. 2003 Jan 23;421(6921):436-40 PMID: 12540918
  71. HIF-1alpha induces cell cycle arrest by functionally counteracting Myc.
    EMBO J. 2004 May 5;23 (9):1949-56 PMID: 15071503
  72. Instability and decay of the primary structure of DNA.
    Nature. 1993 Apr 22;362(6422):709-15 PMID: 8469282
  73. Common fragile sites and cancer (review).
    Int J Oncol. 1998 Jan;12(1):187-96 PMID: 9454904
  74. Decreased growth of Vhl-/- fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27.
    Mol Cell Biol. 2005 Jun;25(11):4565-78 PMID: 15899860
  75. Hypoxia-induced energy stress regulates mRNA translation and cell growth.
    Mol Cell. 2006 Feb 17;21(4):521-31 PMID: 16483933
  76. Common fragile sites and cancer: targeted cloning by insertional mutagenesis.
    Ann N Y Acad Sci. 2004 Dec;1028:14-27 PMID: 15650228
  77. Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH.
    Cancer Res. 2000 Aug 15;60(16):4372-6 PMID: 10969780
  78. Regulation of angiogenesis by hypoxia: role of the HIF system.
    Nat Med. 2003 Jun;9(6):677-84 PMID: 12778166
  79. HIF-1 and tumor progression: pathophysiology and therapeutics.
    Trends Mol Med. 2002;8(4 Suppl):S62-7 PMID: 11927290
  80. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis.
    Genes Dev. 2004 Sep 1;18(17 ):2095-107 PMID: 15314031
  81. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway.
    Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92 PMID: 9653127
  82. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response.
    Cell. 1998 May 1;93(3):477-86 PMID: 9590181
  83. Cancer genes and the pathways they control.
    Nat Med. 2004 Aug;10 (8):789-99 PMID: 15286780
  84. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity.
    Cancer Cell. 2005 Aug;8(2):99-110 PMID: 16098463
  85. Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells.
    Mol Cell Biol. 2003 May;23 (9):3265-73 PMID: 12697826
Article Info
Journal
Journal of molecular medicine (Berlin, Germany)
Abbr.
J Mol Med (Berl)
ISSN
0946-2716
DOI
10.1007/s00109-006-0133-6
Email
eric.huang@hsc.utah.edu
Published
2007-02-00
Epub
2006-00-20
Pages
139-48
Language
English
Region
Germany
NLM ID
9504370
Subset
IM
External Links
PubMed source DOI: 10.1007/s00109-006-0133-6 View journal details
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