• carcinogenesis;
  • chromosomal territory;
  • oxidative DNA damage;
  • ferric nitrilotriacetate;
  • genome


  1. Top of page
  2. Abstract
  7. Acknowledgements

Oxidative stress is associated with inflammation, radiation, reperfusion, and iron overload. Epidemiological observations have shown that oxidative stress is one of the major sources of carcinogenesis, the top-ranked cause of human mortality worldwide. In situations of oxidative stress, reactive oxygen and nitrogen species contribute to the alteration of genome information, presumably followed by selection of the adapted proliferating cells in a given environment. Recent data suggest that common molecular mechanisms exist in oxidative stress-induced carcinogenesis, including p16INK4A inactivation. Thus far, oxidative DNA damage in the genome as a cause of mutation has been recognized to be randomly distributed based on in vitro experiments, while localization of oxidative DNA damage in vivo has not been pursued. However, using a novel technique based on DNA immunoprecipitation in combination with genome information, we now know that the localization of oxidative DNA damage is not random in vivo. We propose to call this rather novel research area “oxygenomics.” Many signaling pathways start from the recognition of DNA damage. Thus, possible underlying principles should be elucidated in association with each cell type, the genomic location of the damage with its transcriptional activity as well as the chromatin status determining the epigenetic effect. © 2008 IUBMB IUBMB Life, 60(7): 441–447, 2008


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  2. Abstract
  7. Acknowledgements

Oxidative stress is associated with a plethora of pathological phenomena, including infection, inflammation, ultraviolet- and γ-irradiation, overload of transition metals and exposure to certain chemical agents as well as ischemia-reperfusion injury1. Many human epidemiological studies have demonstrated a close association between chronically oxidative conditions and carcinogenesis. For example, chronic tuberculous pleuritis causes a high incidence of malignant lymphoma2; asbestosis (some asbestos fibers are rich in iron3) is often associated with mesothelioma and lung carcinoma4; chronic helicobacter pylori infection is associated with a high incidence of gastric cancer5, 6; the incidence of colorectal cancer is increased in ulcerative colitis patients7, 8; a high risk for hepatocellular carcinoma is observed in patients with hereditary hemochromatosis9, 10; severe ultraviolet radiation burns are a risk factor for skin cancer11, 12; and γ-irradiation causes a high incidence of leukemia13. Representative observations are summarized in Table 1. In these circumstances, and probably in other types of carcinogenesis as well, oxidative stress appears to be a key player.

Table 1. Human and animal carcinogenesis presumably associated with oxidative stress
EtiologySpeciesTarget organRepresentative evidence
  1. H, human; M, mouse; MG, Mongolian gerbil; R, rat.

Chemical agents
 Alcohol ethanolH, RLiver14, 15
 Asbestos fiber ironHMesothelium, lung3, 4
 Cigarette smokeHLung16, 17
Metals transition metals except arsenic
Liver, lung, bladder, kidney19, 20
 CadmiumH, RLung, prostate, liver, kidney, stomach21–23
 IronHColon, liver10, 26, 27
 R, MSoft tissue, kidney28–30
 Autoimmune diseases
  Crohn's diseaseHColon31, 32
  Ulcerative colitisH, MColon7, 8
  Helicobacter pyloriH, MGStomach5, 6, 33–35
  Hepatitis C ironHLiver36, 37
  Mycobacterium tuberculosis Lung lymphoma2, 38
 Choline deficiencyRLiver39
Physical agents
 BurnHSkin40, 41
 RadiationHBone marrow13, 42
 UV irradiationH, MSkin11, 12, 43

Cancer is one of the leading causes of death in most well developed countries. It has been established that multiple stepwise alterations of the original genome information are major molecular mechanisms responsible for carcinogenesis44. Excess generation of reactive oxygen and nitrogen species causes DNA single- and double-strand breaks45, crosslinks46, and a variety of other modifications47–49, leading to altered genome information in spite of the robust countermeasures enacted by repair enzymes and apoptotic pathways50. These changes in genetic information are called mutations, and consist of point mutations, deletions, insertions, or chromosomal translocations. These events may cause persistent activation of oncogenes or inactivation of tumor suppressor genes44. After three decades of intensive study to identify the mutated genes (cancer genes) that are causally implicated in carcinogenesis, a “census” of human cancer genes was recently performed. This study indicated that mutations in a little more than 1% of all genes (291 cancer genes) contribute to human cancer (∼80% dominant trait and ∼20% recessive trait). Ninety percent of the cancer genes were somatic mutations in cancer cases, 20% were germline mutations, and 10% were both somatic and germline. The most common functional domain encoded by cancer genes was found to be the protein kinase51.


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  2. Abstract
  7. Acknowledgements

Imatinib mesylate (Gleevec®), a tyrosine kinase inhibitor, has recently achieved success in treating chronic myelogenous leukemia, in which a chimeric oncogene, bcr-abl, is generated via chromosomal translocation52, as well as a sarcoma called gastrointestinal stromal tumor53, 54. On the other hand, recombinant humanized anti-HER2/c-ErbB2/Neu antibody (Herceptin®)55 is clinically used to antagonize the receptor-type tyrosine kinase in invasive ductal carcinoma of the mammary gland56. These are exciting advancements in the understanding of molecular mechanisms of cancer cell proliferation, though the cancer cells may acquire resistance at a later stage57. These achievements stress the importance of the specific signaling pathways established by each cancer type during carcinogenesis.

We must now recognize that these specific signaling pathways have evolved by selective processes during carcinogenesis from thousands of possible mutations to establish a “robust” cellular system58. Thus far, how cells acquire these mutations remains largely unknown. The significance of oxidative stress in carcinogenesis has been established in the past decade, and is summarized in Fig. 1. Of note is the fact that mutation and persistent activation of new signaling pathways for proliferation are cooperative59. Selected mutations of oncogenes generate new signaling pathways for continuous cellular proliferation whereas increased proliferation further enhances the mutation rate. Another suggested mechanism is a “mutator phenotype” in which inactivation of caretaker genes leads to a higher mutation rate, leading to the idea that mutator genes are the first target60. In a sense, carcinogenesis might be compared to evolution; with the difference that carcinogenesis is fatally impatient with regard to time and is mostly associated with somatic cells. Recently, there has been much interest in epigenetic alterations during carcinogenesis in terms of histone modification (acetylation and methylation) and methylation of CpG islands of the promoter region61. Although there is still no convincing data published on the association of oxidative stress and epigenetic alterations, we believe that such interactions should exist considering the close association between oxidative stress and carcinogenesis and the frequent involvement of epigenetic shutting-off mechanisms of tumor suppressor genes during carcinogenesis62.

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Figure 1. Significance of oxidative stress in carcinogenesis.

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Redox regulation is one of the key mechanisms for adaptation to a variety of stresses, including oxidative stress63, 64. Recently, it was reported by several independent laboratories including us that a thioredoxin antagonist (thioredoxin-binding protein-2, TBP-2; also known as vitamin D3 upregulated protein-1, VDUP-1)65 is downregulated in cancers including human adult T-cell leukemia66, 67, human gastric cancer68, 69, and iron (ferric nitrilotriacetate)-induced renal cell carcinoma in rats70. The mechanism of inactivation was consistently methylation of the promoter region. Furthermore, TBP-2 is expressed at higher levels in nonmetastatic melanomas than metastatic melanomas71. Studies of a TBP-2-null mutant mouse72 provided evidence that loss of TBP-2 results in enhanced sulfhydryl reduction and dysregulated carbohydrate and lipid metabolism, namely hyperinsulinemia, hypoglycemia, hypertriglyceridemia and increased levels of ketone bodies, at least in the liver and pancreatic β-cells73. This was confirmed by producing TBP-2-deficient mice74. Loss of TBP-2 appears to be advantageous to cancer cells because it ultimately results in facilitation of the glycolytic pathway via enhancing the enzymatic activity of thioredoxin when we consider the fact that cancer cells are gradually placed in a lower oxygen environment as they form a larger mass75. Indeed, cancer cells in general take up large amounts of glucose76.


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  2. Abstract
  7. Acknowledgements

Most biochemists assume that free radical reactions present little specificity based on in vitro experiments, in contrast with the extremely selective antigen–antibody interactions. Indeed, the second-order rate constant for the reaction of hydroxyl radical with guanine is ∼1.0 × 1010 M−1 sec−11. Thus, one might suppose that the genome is damaged at random and that there are no specific “target” genes or signaling pathways during oxidative stress-induced carcinogenesis. However, it is time to reconsider this assumption. Our laboratory has recently challenged this hypothesis since ferric nitrilotriacetate (Fe-NTA)-induced renal cell carcinomas (RCCs) show rather homogeneous histology77, 78. At an early stage of this rat carcinogenesis model, increased numbers of oxidatively modified DNA bases including 8-oxoguanine79, 80 and a major lipid peroxidation product, 4-hydroxy-2-nonenal, and its modified proteins81–84 are observed. We recently showed using gpt delta transgenic mice that deletion and single nucleotide substitutions at G:C sites are the preferred mutations in the kidney after Fe-NTA administration85.

To clarify whether there is any target tumor suppressor gene, we used a genetic strategy of microsatellite analysis in F1 hybrid rats between two distinct inbred strains86. This study revealed that p15INK4B (p15) and p16INK4A (p16) tumor suppressor genes are among the major target genes, which were either homozygously deleted or methylated at the promoter region. This was the first report showing the presence of a target gene in oxidative stress-induced carcinogenesis62. The significance of this finding is immense, since p16 is associated not only with the retinoblastoma protein pathway as an inhibitor of cyclin-dependent kinase 4 and 6, but also with the TP53 pathway via p19ARF and MDM287, 88. p19ARF is an alternatively spliced transcript from the p16 tumor suppressor gene89. Indeed, iron-mediated oxidative damage appears to attack one of the most critical loci of the genome. Our laboratory later showed that allelic loss of p16 occurs as early as one week after the start of the animal experiment and is p16 gene-specific90. Thereafter, we started to believe in the presence of “fragile” sites in the genome that is susceptible to oxidative stress.

Furthermore, we recently used gene expression microarray and array-based comparative genome hybridization analyses to find target oncogenes in Fe-NTA-induced renal carcinogenesis. At the common chromosomal region of amplification (4q22) in rat RCCs, we found that ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase ζ or receptor tyrosine phosphatase β) is highly expressed in the RCCs. In this model, iron-mediated oxidative stress induced genomic amplification of ptprz1, resulting in activation of β-catenin pathways in the absence of Wnt signaling during carcinogenesis91. Thus, iron-mediated persistent oxidative stress not only confers an environment for gene deletion but also for gene amplification. The current question is whether carcinogenesis is a process of “random alteration of genetic information followed by selective processes” or “nonrandom alteration of genetic information overridden by selective processes.” A final conclusion may change the chemopreventive strategy used for particular circumstances of carcinogenesis.


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  2. Abstract
  7. Acknowledgements

Studying the localization of oxidative nucleic acid damage in comparison with genome information and cellular fundamental structure is becoming increasingly important. There are a number of reports published on oxidative DNA damage in vitro using purified DNA or cultured cells. On the basis of these data, it has been claimed that certain specific sequences including telomeres92, 93 are vulnerable to oxidative damage. However, at present, limited data are available regarding which part of the genome is susceptible to oxidative damage in vivo. The results obtained in vitro must be confirmed, step-by-step, at the tissue and organ levels.

Our laboratory proposes that such studies are now possible given the completion of the genome projects of humans, mice, rats, and other species ( Studies have been performed to make libraries of ∼1 kilobase DNA fragments that contain one or more 8-oxoguanine94 or acrolein-modified adenine95 residues by applying the principle of immunoprecipitation96 (Fig. 2). We must be aware that nuclear genomic DNA in association with histone proteins is integrated into the chromatin structure of the cell, and that some parts of the chromatin structure are open for transcription. Genome information, a blueprint for a cell, is not continuous, but is divided into many pieces that form chromosomes, although chromosomal structure cannot be observed during the interphase. Recently, the concept of “chromosome territory” has been established97, 98. This concept indicates that genome information corresponding to each chromosome is located at a rather fixed site in the nucleus even during interphase, and can be divided into nuclear central or peripheral regions. This localization appears to be different for different kinds of cells99. It is possible that the genome areas susceptible to oxidative stress may differ depending on the kinds of cells and the situations under which the cells are placed. In mouse experiments, we found that the genome corresponding to the nuclear peripherally located chromosome is more susceptible to modification by a lipid peroxidation-associated aldehyde, acrolein96. Such a difference might help explain the different signaling pathways each type of cancer has acquired since several signaling pathways start from the recognition of DNA damage. We propose to call this novel research area “oxygenomics.” Oxygenomics is defined as a research area studying the localization of oxidative DNA damage in the genome of living cells.

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Figure 2. “Oxygenomics” as a means to analyze the in vivo genome DNA status in terms of oxidative stress.

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As described earlier, tailored cancer therapy is now being developed. Cancer prevention100, 101 is no less important than cancer therapy, considering the economic impact of current medical therapeutic costs. In the near future, tailored cancer prevention strategies could become important for medical intervention in medicine when high genetic or environmental risks for certain types of cancer are recognized. We believe that oxygenomics will be an important strategy to discover essential biomarkers for evaluation of the risks and effects in the near future.


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  2. Abstract
  7. Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a MEXT grant (Special Coordination Funds for Promoting Science and Technology), a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan.


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