Article in press - uncorrected proof Biol. Chem., Vol. 387, pp. 365–372, April 2006 • Copyright by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2006.049
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Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammationrelated carcinogenesis
Shosuke Kawanishi1,*, Yusuke Hiraku1, Somchai Pinlaor1,2,3 and Ning Ma4 Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 5148507, Japan 2 Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand 3 Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand 4 Department of Anatomy, Mie University Graduate School of Medicine, Mie 514-8507, Japan 1
* Corresponding author e-mail: kawanisi@doc.medic.mie-u.ac.jp
Abstract Infection and chronic inflammation are proposed to contribute to carcinogenesis through inflammation-related mechanisms. Infection with hepatitis C virus, Helicobacter pylori and the liver fluke, Opisthorchis viverrini (OV), are important risk factors for hepatocellular carcinoma (HCC), gastric cancer and cholangiocarcinoma, respectively. Inflammatory bowel diseases (IBDs) and oral diseases, such as oral lichen planus (OLP) and leukoplakia, are associated with colon carcinogenesis and oral squamous cell carcinoma (OSCC), respectively. We performed a double immunofluorescence labeling study and found that nitrative and oxidative DNA lesion products, 8-nitroguanine and 8-oxo-7,8-dihydro-29-deoxyguanosine (8oxodG), were formed and inducible nitric oxide synthase (iNOS) was expressed in epithelial cells and inflammatory cells at the site of carcinogenesis in humans and animal models. Antibacterial, antiviral and antiparasitic drugs dramatically diminished the formation of these DNA lesion markers and iNOS expression. These results suggest that oxidative and nitrative DNA damage occurs at the sites of carcinogenesis, regardless of etiology. Therefore, it is considered that excessive amounts of reactive nitrogen species produced via iNOS during chronic inflammation may play a key role in carcinogenesis by causing DNA damage. On the basis of our results, we propose that 8-nitroguanine is a promising biomarker to evaluate the potential risk of inflammation-mediated carcinogenesis. Keywords: carcinogenesis; DNA damage; inducible nitric oxide synthase; inflammation; 8-nitroguanine; 8-oxo-7,8-dihydro-29-deoxyguanosine.
Introduction Recently, experimental and epidemiological evidence indicates that a variety of infectious agents constitute one of the main causes of cancer (Coussens and Werb, 2002; IARC, 2003). The International Agency for Research on Cancer (IARC) has estimated that approximately 18% of cancer cases worldwide are attributable to infectious diseases (IARC, 2003). The burden of cancer caused by infectious agents is shown in Table 1. Viruses, bacteria and parasites can cause chronic inflammation and contribute to 1.6 million cases of infectionrelated malignancies per year. Inflammation can be induced not only by chronic infection, but also by many other physical, chemical and immunological factors (Coussens and Werb, 2002; Ohshima et al., 2003). It has been hypothesized that many malignancies arise from areas of infection and inflammation (Balkwill and Mantovani, 2001; Coussens and Werb, 2002). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are capable of causing damage to various cellular constituents, such as nucleic acids, proteins and lipids. ROS and RNS are considered to play an important role in carcinogenesis through oxidative and nitrative DNA damage (Hussain et al., 2003; Ohshima et al., 2003). ROS can induce the formation of oxidative DNA lesion products, including 8-oxo-7,8-dihydro-29-deoxyguanosine (8-oxodG) (Wiseman and Halliwell, 1996; Burrows and Muller, 1998; Kawanishi et al., 2001; Evans et al., 2004), which is considered to be mutagenic. It has been reported that misincorporation of adenine occurs opposite 8-oxodG during DNA synthesis, leading to G™T transversions (Shibutani et al., 1991; Bruner et al., 2000). ROS are generated from multiple sources, including inflammatory cells, as well as carcinogenic chemicals and their metabolites and the electron transport chain in mitochondria. On the other hand, nitric oxide (NO) is generated specifically during inflammation via inducible nitric oxide synthase (iNOS) in inflammatory and epithelial cells (Figure 1). Excess NO production plays a crucial role in an enormous variety of pathological processes, including cancer (Hussain et al., 2003; Ohshima et al., 2003). NO reacts with superoxide (O2•-) to form peroxynitrite (ONOO-), a highly reactive species causing nitrative and oxidative DNA damage. ONOO- can mediate the formation of 8oxodG (Inoue and Kawanishi, 1995) and 8-nitroguanine, a marker of nitrative DNA damage (Yermilov et al., 1995). Akaike et al. (2003) demonstrated that 8-nitroguanine is formed via NO production associated with inflammation in mice with viral pneumonia. 8-Nitroguanine is consid-
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Table 1 The burden of cancer caused by infectious agents worldwide (adapted from the IARC World Cancer Report; IARC, 2003). Infectious agent
IARC classificationa
Cancer site
Bacterial infection H. pylori
1
Stomach
490 000
5.4
Viral infection HPV HBV, HCV EBV
1, 2A 1 1
550 000 390 000 99 000
6.1 4.3 1.1
2A 1
Cervix and other sites Liver Lymphoma, nasopharyngeal carcinoma Kaposi sarcoma Leukemia
54 000 9 000
0.6 0.1
1
Bladder
2 700
0.1
1 2A
Intra- and extrahepatic bile ducts
HHV-8 HTLV-1 Parasitic infection Schistosoma haematobium Liver flukes Opisthorchis viverrini Clonorchis sinensis Total infection-related cancers Total cancers in 1995
Number of cancer cases
Percentage of cancer cases worldwide (%)
800
1 600 000 9 000 000
17.7 100
Group 1, carcinogenic to humans; Group 2A, probably carcinogenic to humans.
a
ered to be not only a marker of inflammation, but also a potential mutagenic DNA lesion product, leading to carcinogenesis. 8-Nitroguanine formed in DNA is chemically unstable, and thus can be spontaneously released, resulting in the formation of an apurinic site (Yermilov et al., 1995). The apurinic site can form a pair with adenine during DNA synthesis, leading to G™T transversions (Loeb and Preston, 1986; Figure 1). A recent study has revealed that the activity of APE1, the major apurinicsite endonuclease, was significantly increased in colon epithelium displaying elevated inflammation in patients
with ulcerative colitis (Hofseth et al., 2003a). Apurinic sites might represent the major lesion that requires errorprone DNA polymerase z for efficient trans-lesion DNA synthesis. DNA polymerase z can efficiently bypass abasic sites by extending from nucleotides inserted opposite the lesion by other DNA polymerase (Haracska et al., 2001). Cells deficient in subunits of DNA polymerase z were hypersensitive to nitrative stress, and trans-lesion DNA synthesis past apurinic sites mediated by this polymerase might contribute to extensive point mutations (Wu et al., 2006). Recently, it has been reported that in a
Figure 1 Proposed mechanism for mutation via 8-nitroguanine formation induced by inflammation.
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Figure 2 Double immunofluorescent staining of 8-oxodG and 8-nitroguanine in the liver of OV-infected hamsters. Immunoreactivities of 8-oxodG and 8-nitroguanine were investigated in the same inflammatory cells and epithelium of bile ducts. The immunoreactivities of these DNA lesions remained in the epithelium of bile duct on day 90, and increased with the frequency of OV infection. Inset: inflammatory cells in which 8-oxodG and 8-nitroguanine are colocalized on day 14. Arrow: multinuclear giant cell in which only 8-oxodG is formed. 8-NG, 8-nitroguanine. Scale bar represents 50 mm. Methods: To examine the distribution of 8-nitroguanine, a highly sensitive and specific anti-8-nitroguanine antibody without crossreaction with other related compounds, such as 3-nitrotyrosine, 8-bromoguanine and 8-oxodG, was used (Pinlaor et al., 2004a). 8Nitroguanine aldehyde-rabbit serum albumin conjugate was intracutaneously injected into a rabbit. The antibody was purified from the blood by affinity chromatography. The specificity of the purified antibody was examined by a dot immunobinding assay and absorption test as previously described (Pinlaor et al., 2004a). Double immunofluorescence labeling studies of 8-nitroguanine and 8oxodG were performed using tissues obtained from hamsters with OV infection. Deparaffinized paraffin sections were treated with rabbit polyclonal anti-8-nitroguanine antibody and mouse monoclonal anti-8-oxodG antibody. They were then incubated with Alexa 594-labeled goat antibody against rabbit IgG and Alexa 488-labeled goat antibody against mouse IgG. The immunostained sections were examined by confocal microscopy.
cell-free system, adenine is preferentially incorporated opposite 8-nitroguanine during DNA synthesis mediated by DNA polymerase h and k associated with trans-lesion DNA synthesis, suggesting that G™T transversions can also occur via this mechanism (Suzuki et al., 2005). In the ONOO--treated supF shuttle vector plasmid, which was then replicated in Escherichia coli, the majority of mutations occurred at G:C base pairs, predominantly involving G™T transversions (Juedes and Wogan, 1996; Kim et al., 2005). Therefore, 8-nitroguanine is a potentially mutagenic DNA lesion product leading to carcinogenesis, as well as 8-oxodG. In particular, we have proposed the possibility that 8-nitroguanine is a potential biomarker for evaluating the risk of inflammation-related carcinogenesis. Here we discuss the role of oxidative and nitrative DNA damage in carcinogenesis caused by chronic inflammation.
DNA damage in animal models of inflammation-related carcinogenesis Liver fluke infection and cholangiocarcinoma Infection with the liver fluke Opisthorchis viverrini (OV) is a major risk factor for cholangiocarcinoma, especially in
the north-eastern region of Thailand (Haswell-Elkins et al., 1994; IARC Working Group, 1994b). Approximately 70% of OV-induced cholangiocarcinomas occur in the intrahepatic bile ducts, and the remainder occur in the extrahepatic duct (Uttararvichen et al., 1996). We investigated DNA damage in the liver of hamsters with single and repeated OV infection as a model of inflammationrelated carcinogenesis in humans. We first demonstrated that 8-nitroguanine is formed in relation to inflammationrelated carcinogenesis using OV-infected hamsters (Pinlaor et al., 2003). Double immunofluorescence staining revealed that 8-oxodG and 8-nitroguanine were formed in inflammatory cells and epithelium of bile ducts (Pinlaor et al., 2004a,b). The immunoreactivities of 8-oxodG and 8-nitroguanine in inflammatory cells were most prominently observed on days 21 and 30, respectively (Pinlaor et al., 2004a). Interestingly, these DNA lesion products still remained in the epithelium of bile ducts on day 180 (Pinlaor et al., 2004a). The formation of 8-nitroguanine and 8-oxodG increased in the epithelium of bile ducts in the order of triple infection ) double infection ) single infection (Pinlaor et al., 2004b; Figure 2). This may be explained by the fact that repeated infection increased iNOS expression in the epithelium of bile ducts in the same order (Pinlaor et al., 2004b). The treatment of
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OV-infected hamsters with the antihelminthic drug praziquantel dramatically diminished the formation of 8nitroguanine and 8-oxodG, and iNOS expression (Pinlaor et al., 2006). Proliferating cell nuclear antigen (PCNA), which functions as a cofactor for DNA polymerase d, is associated with DNA replication and long-patch base excision repair (Schipper et al., 1998; Evans et al., 2004). In our study, PCNA accumulated in the epithelium of bile ducts after repeated OV infection, supporting the hypothesis that cell proliferation was promoted by inflammationmediated DNA damage (Pinlaor et al., 2004b). Recently, we have reported that OV antigen induces an inflammatory response, including activation of nuclear factor kB (NF-kB) and expression of iNOS, in a mouse macrophage cell line through a Toll-like receptor (TLR)-2mediated pathway (Pinlaor et al., 2005b). Moreover, strong TLR2 expression was also observed in bile duct epithelial cells and inflammatory cells of the liver of OVinfected hamsters (Pinlaor et al., 2006). TLRs activate homologous signal transduction pathways, leading to nuclear localization of NF-kB/Rel-type transcription factors (O’Neill and Greene, 1998). NF-kB is a key player in inflammation that regulates the expression of various genes involved in controlling inflammatory response, including iNOS expression (Surh et al., 2001). Importantly, NF-kB functions as a tumor promoter in inflammationassociated cancer (Pikarsky et al., 2004). Our recent epidemiological study on cholangiocarcinoma patients demonstrated that the formation of 8oxodG and 8-nitroguanine occurred to a much greater extent in cancerous tissue than in the adjacent non-cancerous intrahepatic tissue and that these DNA lesion products may contribute to tumor progression (Pinlaor et al., 2005a). Collectively, more frequent OV infection can induce more prominent iNOS expression in bile duct epithelial cells and inflammatory cells via TLR2 expression, resulting in nitrative and oxidative damage to nucleic acids, which may participate in every step of cholangiocarcinoma development, including initiation, promotion and progression (Figure 3). Inflammatory bowel disease and colon cancer Ulcerative colitis and Crohn’s disease, which are referred to as inflammatory bowel diseases (IBDs), are well known as chronic inflammatory diseases in the lower bowel. Epidemiological studies have shown that the incidence of colorectal cancer in IBD is greater than the expected incidence in the general population (Ekbom et al., 1990). Although the precise mechanisms of the pathogenesis of IBD have not been clarified, a large number of immunological abnormalities have been noted in patients with IBD (Podolsky, 2002; Bouma and Strober, 2003). Inflammation occurs as a result of either excessive functions of effector T-cells, such as T-helper type 1 (Th1) and 2 (Th2) cells, or deficient function of regulatory T-cells (Figure 4A). On the basis of the hypothesis that an imbalance of helper and regulatory T-cell functions plays a key role in IBD pathogenesis, we prepared a mouse model of IBD as previously described (Powrie et al., 1993; Ding et al., 2005). Figure 4B shows the procedure for producing this mouse model. CD4q T-cells were isolated from single-cell
Figure 3 Proposed mechanism for carcinogenesis via oxidative and nitrative DNA damage induced by OV infection.
suspensions of spleen from BALB/c mice by negative selection, and then CD45RBhighCD4q T-cells were positively selected using AutoMACS after staining with FITCconjugated anti-CD45RB monoclonal antibody followed by anti-FITC-conjugated microbeads. For induction of IBD, C.B-17 SCID mice were injected intraperitoneally with purified CD45RBhighCD4q T-cells. Mice of this IBD model showed a lower increase in body weight with aging than non-treated controls and the intestine was shortened. These mice developed clinical signs of colitis, including diarrhea and weight loss. Pathological findings in the mice, which showed severe inflammation in colon tissues, were similar to IBD patients. Double immunofluorescence revealed that both 8nitroguanine and 8-oxodG were mainly formed in epithelial cells of the IBD mouse model (Ding et al., 2005). When tissue sections were pretreated with RNase, 8-nitroguanine immunoreactivity was more clearly observed in the nuclei of epithelial cells, suggesting that 8-nitroguanine is formed mainly in genomic DNA. The formation of 8-nitroguanine in nuclei was confirmed by electron microscopic immunohistochemistry. iNOS, PCNA and p53 proteins were also expressed in colon epithelium. We also demonstrated that 8-nitroguanine was formed in colon epithelium of patients with ulcerative colitis (unpublished data). Of relevance, several studies have shown that iNOS is expressed in epithelial cells in colitis patients (Singer et al., 1996; Wiseman and Halli-
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Figure 4 Hypothesis for the pathogenesis of IBD and preparation of a mouse model. It has been hypothesized that an imbalance of helper and regulatory T-cell functions plays a key role in IBD pathogenesis (A). To prepare a mouse model of IBD, CD45RBhighCD4q T-cells (mainly consisting of Th1- and Th2-cells) were isolated from the spleen of BALB/c mice, and then injected intraperitoneally into C.B-17 SCID mice.
well, 1996; Hofseth et al., 2003b). In non-cancerous colon tissues from patients with ulcerative colitis, iNOS protein levels were positively correlated with p53 serine 15 phosphorylation levels (Hofseth et al., 2003b). These results suggest that nitrative DNA damage, as well as oxidative DNA damage, participates in colon carcinogenesis in patients with IBD.
DNA damage in patients with inflammatory diseases Helicobacter pylori infection and gastric cancer Infection with the Gram-negative bacterium Helicobacter pylori is not only associated with chronic atrophic gastritis and peptic ulcer, but also with gastric adenocarcinoma and non-Hodgkin’s lymphoma wmucosa-associated lymphoid tissue (MALT) lymphomax (Peek and Blaser, 2002). In 2005, Barry Marshall and Robin Warren were awarded with the Nobel Prize for discovery of H. pylori. To examine whether nitrative and oxidative DNA damage plays a role in the carcinogenic process triggered by H. pylori infection, we performed a double immunofluorescence labeling study using biopsy specimens of gastric mucosa. Intense immunoreactivities of 8-nitroguanine and 8-oxodG were observed in both gastric gland epithelial cells and inflammatory cells in patients with H. pylori infection (Ma et al., 2004). On the other hand, in gastritis patients without H. pylori infection, these immunoreactivities were observed mainly in inflammatory cells, and not in gastric gland epithelial cells. This is the first report showing that 8-nitroguanine is formed in humans in relation to inflammation-related
carcinogenesis. Moreover, we found that 8-nitroguanine formation in patients with H. pylori infection was dramatically decreased by eradication (unpublished data). The mechanisms by which H. pylori infection causes gastric cancer have been investigated. Lipopolysaccharide (LPS), a component of Gram-negative bacteria, including H. pylori, is a ligand of TLR4. TLR4 is involved in activation of the transcription factor NF-kB (Maeda et al., 2001), which mediates expression of iNOS and various inflammatory cytokines. Alternatively, the Cag-positive H. pylori strain induces an intense inflammatory response, including interleukin (IL)-8 production by epithelial cells and subsequent production of tumor necrosis factor (TNF)-a by inflammatory cells (Peek and Blaser, 2002). The host immune response to H. pylori mediated by cytokines, resulting in iNOS expression, may lead to an increase in the accumulation of 8-nitroguanine and 8-oxodG in gastric epithelium. Several studies have demonstrated that PCNA is an independent prognostic factor for gastric cancer in patients with H. pylori infection (Schipper et al., 1998). In our study, accumulation of PCNA was observed in gastric gland epithelial cells in patients with H. pylori infection (Ma et al., 2004). These results suggest that nitrative and oxidative DNA damage in gastric epithelial cells and their proliferation by H. pylori infection may lead to gastric carcinoma. Hepatitis C virus infection and liver cancer Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma throughout the world (IARC Working Group, 1994a; Poynard et al., 2003). Hepatocellular carcinoma arises
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through a multistep process of genetic alterations in hepatocytes during chronic hepatitis C (CHC) (Bressac et al., 1991; Hsu et al., 1991; Oda et al., 1992; Caselmann and Alt, 1996). However, the mechanism of HCV infection-induced hepatitis followed by hepatocarcinogenesis via DNA damage is still unclear. We investigated DNA damage in liver biopsy specimens from patients with CHC and the effect of interferon treatment. Immunoreactivities of 8-nitroguanine and 8oxodG were strongly detected in liver from patients with CHC, but not in control livers (non-alcoholic fatty liver) (Horiike et al., 2005). 8-Nitroguanine formation was found not only in infiltrating inflammatory cells, but also in hepatocytes, particularly in the periportal area. The accumulation of 8-nitroguanine and 8-oxodG increased with inflammatory grade. iNOS expression was observed in the cytoplasm of hepatocytes and Kupffer cells in CHC patients. In the sustained virological responder group after interferon therapy, accumulation of 8-nitroguanine and 8-oxodG in the liver was markedly decreased (Horiike et al., 2005). Histological examination showed more prominent inflammatory changes in CHC patients than in control patients, and these changes were improved after interferon therapy. Our results are consistent with previous reports showing that iNOS was expressed in hepatocytes of patients with chronic hepatitis (McNaughton et al., 2002) and hepatocellular carcinoma (Rahman et al., 2001). Taken together, these findings indicate that 8-nitroguanine is a useful biomarker for evaluating the severity of HCV-induced chronic inflammation leading to hepatocellular carcinoma and the efficacy of CHC treatment. Oral lichen planus, oral cancer and leukoplakia Oral lichen planus (OLP) is a chronic inflammatory mucosal disease (Scully et al., 1998). Several pathological features indicate that OLP is an immunologically mediated inflammatory response, including an intense, band-like infiltrate of predominantly T-lymphocytes subjacent to epithelium. Basal epithelial cells are the target for immune destruction by cytotoxic T-lymphocytes (Tyldesley and Appleton, 1973; Dekker et al., 1997). The most important complication of OLP is development of oral squamous cell carcinoma (OSCC) (Rajentheran et al., 1999; Mignogna et al., 2004). Oral leukoplakia is a precancerous lesion characterized by white plaque and hyperkeratosis (Neville and Day, 2002; Reibel, 2003), with 5–15% of leukoplakia histologically classified as dysplasia (Suarez et al., 1998; Sudbo and Reith, 2005). A substantial proportion of dysplasia is reported to develop into oral carcinoma (Lumerman et al., 1995; Sudbo and Reith, 2005). However, DNA damage associated with these oral diseases has not been investigated. We demonstrated that accumulation of 8-nitroguanine and 8-oxodG was observed in oral epithelium of biopsy specimens from patients with OLP and OSCC, whereas no immunoreactivity was observed in normal oral mucosa (Chaiyarit et al., 2005). 8-Nitroguanine and 8-oxodG were also observed in oral epithelium of patients with leukoplakia (Ma et al., 2006). Colocalization of 8-nitroguanine and iNOS was found in oral epithelium of patients with OLP, OSCC and leukoplakia. Immunoreac-
tivity of 3-nitrotyrosine, which is formed by protein tyrosine nitration and considered to be a biochemical marker for inflammation, was also observed in oral epithelial cells. Accumulation of p53 was observed in oral epithelium in OLP and leukoplakia, and more prominent expression of this protein was observed in OSCC patients. Our findings demonstrate that iNOS-dependent DNA damage may lead to p53 accumulation not only in OLP and leukoplakia, but also in OSCC. It is concluded that the formation of 8-nitroguanine and 8-oxodG may contribute to the development of oral cancer from OLP and leukoplakia.
Conclusion In relation to inflammation-related carcinogenesis, we examined the formation of 8-nitroguanine and 8-oxodG in experimental animal models. DNA damage was specifically induced at sites of carcinogenesis under various inflammatory conditions. In hamsters infected with the liver fluke OV causing cholangiocarcinoma, 8-nitroguanine formation was induced in bile duct epithelium (Pinlaor et al., 2004b). Moreover, 8-nitroguanine was formed in colonic gland epithelial cells in a mouse model of IBD (Ding et al., 2005). It is noteworthy that 8-nitroguanine formation was also observed in human samples. 8-Nitroguanine was formed in gastric gland epithelial cells of patients with H. pylori infection (Ma et al., 2004) and in hepatocytes of patients with chronic hepatitis C (Horiike et al., 2005). 8-Nitroguanine was also formed in oral epithelium of patients with OLP, OSCC (Chaiyarit et al., 2005) and leukoplakia (Ma et al., 2006). Therefore, 8nitroguanine could be used as a potential biomarker of inflammation-related carcinogenesis. Establishment of methods for quantitative analysis of 8-nitroguanine in biological or clinical specimens could be useful for evaluating the risk of carcinogenesis. However, 8-nitroguanine formed in DNA is chemically unstable, and this characteristic may hamper its quantitative analysis. Therefore, free 8-nitroguanine released from DNA in urine might be available for quantification as a biomarker. In addition, measurement of 8-nitroguanosine derived from 8-nitroguanine-bound RNA in clinical specimens, including white blood cells, may be useful for evaluation of carcinogenic potential. Recently, 8-nitroguanosine has been reported to be a highly redox-active molecule (Sawa et al., 2003; Zaki et al., 2005). More importantly, experimental evidence has suggested that 8-nitroguanine is a mutagenic DNA lesion, which preferentially leads to G™T transversions (Yermilov et al., 1995; Suzuki et al., 2005), in addition to 8-oxodG (Shibutani et al., 1991; Bruner et al., 2000). Indeed, G™T transversions have been observed in vivo in the ras gene (Bos, 1988) and the p53 tumor suppressor gene in lung and liver cancer (Takahashi et al., 1989; Hsu et al., 1991). These findings imply that DNA damage mediated by ROS and RNS may participate in carcinogenesis via activation of proto-oncogenes and inactivation of tumor suppressor genes. In conclusion, oxidative and nitrative DNA damage could represent promising
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biomarkers for evaluating the risk of inflammation-related carcinogenesis.
References Akaike, T., Okamoto, S., Sawa, T., Yoshitake, J., Tamura, F., Ichimori, K., Miyazaki, K., Sasamoto, K., and Maeda, H. (2003). 8-Nitroguanosine formation in viral pneumonia and its implication for pathogenesis. Proc. Natl. Acad. Sci. USA 100, 685–690. Balkwill, F. and Mantovani, A. (2001). Inflammation and cancer: back to Virchow? Lancet 357, 539–545. Bos, J.L. (1988). The ras gene family and human carcinogenesis. Mutat. Res. 195, 255–271. Bouma, G. and Strober, W. (2003). The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol. 3, 521–533. Bressac, B., Kew, M., Wands, J., and Ozturk, M. (1991). Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429–431. Bruner, S.D., Norman, D.P., and Verdine, G.L. (2000). Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403, 859–866. Burrows, C.J. and Muller, J.G. (1998). Oxidative nucleobase modifications leading to strand scission. Chem. Rev. 98, 1109–1151. Caselmann, W.H. and Alt, M. (1996). Hepatitis C virus infection as a major risk factor for hepatocellular carcinoma. J. Hepatol. 24, 61–66. Chaiyarit, P., Ma, N., Hiraku, Y., Pinlaor, S., Yongvanit, P., Jintakanon, D., Murata, M., Oikawa, S., and Kawanishi, S. (2005). Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis. Cancer Sci. 96, 553–559. Coussens, L.M. and Werb, Z. (2002). Inflammation and cancer. Nature 420, 860–867. Dekker, N.P., Lozada-Nur, F., Lagenaur, L.A., MacPhail, L.A., Bloom, C.Y., and Regezi, J.A. (1997). Apoptosis-associated markers in oral lichen planus. J. Oral Pathol. Med. 26, 170–175. Ding, X., Hiraku, Y., Ma, N., Kato, T., Saito, K., Nagahama, M., Semba, R., Kuribayashi, K., and Kawanishi, S. (2005). Inducible nitric oxide synthase-dependent DNA damage in mouse model of inflammatory bowel disease. Cancer Sci. 96, 157–163. Ekbom, A., Helmick, C., Zack, M., and Adami, H.O. (1990). Increased risk of large-bowel cancer in Crohn’s disease with colonic involvement. Lancet 336, 357–359. Evans, M.D., Dizdaroglu, M., and Cooke, M.S. (2004). Oxidative DNA damage and disease: induction, repair and significance. Mutat. Res. 567, 1–61. Haracska, L., Unk, I., Johnson, R.E., Johansson, E., Burgers, P.M., Prakash, S., and Prakash, L. (2001). Roles of yeast DNA polymerases d and z and of Rev1 in the bypass of abasic sites. Genes Dev. 15, 945–954. Haswell-Elkins, M.R., Mairiang, E., Mairiang, P., Chaiyakum, J., Chamadol, N., Loapaiboon, V., Sithithaworn, P., and Elkins, D.B. (1994). Cross-sectional study of Opisthorchis viverrini infection and cholangiocarcinoma in communities within a high-risk area in northeast Thailand. Int. J. Cancer 59, 505–509. Hofseth, L.J., Khan, M.A., Ambrose, M., Nikolayeva, O., Xu-Welliver, M., Kartalou, M., Hussain, S.P., Roth, R.B., Zhou, X., Mechanic, L.E., et al. (2003a). The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation. J. Clin. Invest. 112, 1887–1894. Hofseth, L.J., Saito, S., Hussain, S.P., Espey, M.G., Miranda, K.M., Araki, Y., Jhappan, C., Higashimoto, Y., He, P., Linke, S.P., et al. (2003b). Nitric oxide-induced cellular stress and
p53 activation in chronic inflammation. Proc. Natl. Acad. Sci. USA 100, 143–148. Horiike, S., Kawanishi, S., Kaito, M., Ma, N., Tanaka, H., Fujita, N., Iwasa, M., Kobayashi, Y., Hiraku, Y., Oikawa, S., et al. (2005). Accumulation of 8-nitroguanine in the liver of patients with chronic hepatitis C. J. Hepatol. 43, 403–410. Hsu, I.C., Metcalf, R.A., Sun, T., Welsh, J.A., Wang, N.J., and Harris, C.C. (1991). Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350, 427–428. Hussain, S.P., Hofseth, L.J., and Harris, C.C. (2003). Radical causes of cancer. Nat. Rev. Cancer 3, 276–285. IARC (2003). Chronic infections. In: World Cancer Report, B.W. Stewart and P. Kleihues, eds. (Lyon, France: IARC Press), pp. 56–61. IARC Working Group (1994a). Hepatitis C virus. IARC Monogr. Eval. Carcinog. Risks Hum. 59, 165–221. IARC Working Group (1994b). Infection with liver flukes (Opisthorchis viverrini, Opisthorchis felineus and Clonorchis sinensis). IARC Monogr. Eval. Carcinog. Risks Hum. 61, 121–175. Inoue, S. and Kawanishi, S. (1995). Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBS Lett. 371, 86–88. Juedes, M.J. and Wogan, G.N. (1996). Peroxynitrite-induced mutation spectra of pSP189 following replication in bacteria and in human cells. Mutat. Res. 349, 51–61. Kawanishi, S., Hiraku, Y., and Oikawa, S. (2001). Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. Mutat. Res. 488, 65–76. Kim, M.Y., Dong, M., Dedon, P.C., and Wogan, G.N. (2005). Effects of peroxynitrite dose and dose rate on DNA damage and mutation in the supF shuttle vector. Chem. Res. Toxicol. 18, 76–86. Loeb, L.A. and Preston, B.D. (1986). Mutagenesis by apurinic/ apyrimidinic sites. Annu. Rev. Genet. 20, 201–230. Lumerman, H., Freedman, P., and Kerpel, S. (1995). Oral epithelial dysplasia and the development of invasive squamous cell carcinoma. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 79, 321–329. Ma, N., Adachi, Y., Hiraku, Y., Horiki, N., Horiike, S., Imoto, I., Pinlaor, S., Murata, M., Semba, R., and Kawanishi, S. (2004). Accumulation of 8-nitroguanine in human gastric epithelium induced by Helicobacter pylori infection. Biochem. Biophys. Res. Commun. 319, 506–510. Ma, N., Tagawa, T., Hiraku, Y., Murata, M., Ding, X., and Kawanishi, S. (2006). 8-Nitroguanine formation in oral leukoplakia, a premalignant lesion. Nitric Oxide 14, 137–143. Maeda, S., Akanuma, M., Mitsuno, Y., Hirata, Y., Ogura, K., Yoshida, H., Shiratori, Y., and Omata, M. (2001). Distinct mechanism of Helicobacter pylori-mediated NF-kB activation between gastric cancer cells and monocytic cells. J. Biol. Chem. 276, 44856–44864. McNaughton, L., Puttagunta, L., Martinez-Cuesta, M.A., Kneteman, N., Mayers, I., Moqbel, R., Hamid, Q., and Radomski, M.W. (2002). Distribution of nitric oxide synthase in normal and cirrhotic human liver. Proc. Natl. Acad. Sci. USA 99, 17161–17166. Mignogna, M.D., Fedele, S., Lo Russo, L., Lo Muzio, L., and Bucci, E. (2004). Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence? Oral Oncol. 40, 120–130. Neville, B.W., and Day, T.A. (2002). Oral cancer and precancerous lesions. CA Cancer J. Clin. 52, 195–215. Oda, T., Tsuda, H., Scarpa, A., Sakamoto, M., and Hirohashi, S. (1992). p53 gene mutation spectrum in hepatocellular carcinoma. Cancer Res. 52, 6358–6364. Ohshima, H., Tatemichi, M., and Sawa, T. (2003). Chemical basis of inflammation-induced carcinogenesis. Arch. Biochem. Biophys. 417, 3–11. O’Neill, L.A., and Greene, C. (1998). Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants. J. Leukoc. Biol. 63, 650–657.
Article in press - uncorrected proof 372 S. Kawanishi et al.
Peek Jr., R.M., and Blaser, M.J. (2002). Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat. Rev. Cancer 2, 28–37. Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., and Ben-Neriah, Y. (2004). NF-kB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466. Pinlaor, S., Yongvanit, P., Hiraku, Y., Ma, N., Semba, R., Oikawa, S., Murata, M., Sripa, B., Sithithaworn, P., and Kawanishi, S. (2003). 8-Nitroguanine formation in the liver of hamsters infected with Opisthorchis viverrini. Biochem. Biophys. Res. Commun. 309, 567–571. Pinlaor, S., Hiraku, Y., Ma, N., Yongvanit, P., Semba, R., Oikawa, S., Murata, M., Sripa, B., Sithithaworn, P., and Kawanishi, S. (2004a). Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchis viverrini: a model of inflammation-mediated carcinogenesis. Nitric Oxide 11, 175–183. Pinlaor, S., Ma, N., Hiraku, Y., Yongvanit, P., Semba, R., Oikawa, S., Murata, M., Sripa, B., Sithithaworn, P., and Kawanishi, S. (2004b). Repeated infection with Opisthorchis viverrini induces accumulation of 8-nitroguanine and 8-oxo-7,8-dihydro-29deoxyguanine in the bile duct of hamsters via inducible nitric oxide synthase. Carcinogenesis 25, 1535–1542. Pinlaor, S., Sripa, B., Ma, N., Hiraku, Y., Yongvanit, P., Wongkham, S., Pairojkul, C., Bhudhisawasdi, V., Oikawa, S., Murata, M., et al. (2005a). Nitrative and oxidative DNA damage in intrahepatic cholangiocarcinoma patients in relation to tumor invasion. World J. Gastroenterol. 11, 4644–4649. Pinlaor, S., Tada-Oikawa, S., Hiraku, Y., Pinlaor, P., Ma, N., Sithithaworn, P., and Kawanishi, S. (2005b). Opisthorchis viverrini antigen induces the expression of Toll-like receptor 2 in macrophage RAW cell line. Int. J. Parasitol. 35, 591–596. Pinlaor, S., Hiraku, Y., Yongvanit, P., Tada-Oikawa, S., Ma, N., Pinlaor, P., Sithithaworn, P., Sripa, B., Marata, M., Oikawa, S., and Kawanishi, S. (2006). iNOS-dependent DNA damage via NF-kB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel. Int. J. Cancer, in press. Podolsky, D.K. (2002). Inflammatory bowel disease. N. Engl. J. Med. 347, 417–429. Powrie, F., Leach, M.W., Mauze, S., Caddle, L.B., and Coffman, R.L. (1993). Phenotypically distinct subsets of CD4q T cells induce or protect from chronic intestinal inflammation in C.B17 scid mice. Int. Immunol. 5, 1461–1471. Poynard, T., Yuen, M.F., Ratziu, V., and Lai, C.L. (2003). Viral hepatitis C. Lancet 362, 2095–2100. Rahman, M.A., Dhar, D.K., Yamaguchi, E., Maruyama, S., Sato, T., Hayashi, H., Ono, T., Yamanoi, A., Kohno, H., and Nagasue, N. (2001). Coexpression of inducible nitric oxide synthase and COX-2 in hepatocellular carcinoma and surrounding liver: possible involvement of COX-2 in the angiogenesis of hepatitis C virus-positive cases. Clin. Cancer Res. 7, 1325–1332. Rajentheran, R., McLean, N.R., Kelly, C.G., Reed, M.F., and Nolan, A. (1999). Malignant transformation of oral lichen planus. Eur. J. Surg. Oncol. 25, 520–523. Reibel, J. (2003). Prognosis of oral pre-malignant lesions: significance of clinical, histopathological, and molecular biological characteristics. Crit. Rev. Oral Biol. Med. 14, 47–62.
Sawa, T., Akaike, T., Ichimori, K., Akuta, T., Kaneko, K., Nakayama, H., Stuehr, D.J., and Maeda, H. (2003). Superoxide generation mediated by 8-nitroguanosine, a highly redox-active nucleic acid derivative. Biochem. Biophys. Res. Commun. 311, 300–306. Schipper, D.L., Wagenmans, M.J., Peters, W.H., and Wagener, D.J. (1998). Significance of cell proliferation measurement in gastric cancer. Eur. J. Cancer 34, 781–790. Scully, C., Beyli, M., Ferreiro, M.C., Ficarra, G., Gill, Y., Griffiths, M., Holmstrup, P., Mutlu, S., Porter, S., and Wray, D. (1998). Update on oral lichen planus: etiopathogenesis and management. Crit. Rev. Oral Biol. Med. 9, 86–122. Shibutani, S., Takeshita, M., and Grollman, A.P. (1991). Insertion of specific bases during DNA synthesis past the oxidationdamaged base 8-oxodG. Nature 349, 431–434. Singer, I.I., Kawka, D.W., Scott, S., Weidner, J.R., Mumford, R.A., Riehl, T.E., and Stenson, W.F. (1996). Expression of inducible nitric oxide synthase and nitrotyrosine in colonic epithelium in inflammatory bowel disease. Gastroenterology 111, 871– 885. Suarez, P., Batsakis, J.G., and el-Naggar, A.K. (1998). Leukoplakia: still a gallimaufry or is progress being made? – A review. Adv. Anat. Pathol. 5, 137–155. Sudbo, J. and Reith, A. (2005). The evolution of predictive oncology and molecular-based therapy for oral cancer prevention. Int. J. Cancer 115, 339–345. Surh, Y.J., Chun, K.S., Cha, H.H., Han, S.S., Keum, Y.S., Park, K.K., and Lee, S.S. (2001). Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kB activation. Mutat. Res. 480/481, 243–268. Suzuki, N., Yasui, M., Geacintov, N.E., Shafirovich, V., and Shibutani, S. (2005). Miscoding events during DNA synthesis past the nitration-damaged base 8-nitroguanine. Biochemistry 44, 9238–9245. Takahashi, T., Nau, M.M., Chiba, I., Birrer, M.J., Rosenberg, R.K., Vinocour, M., Levitt, M., Pass, H., Gazdar, A.F., and Minna, J.D. (1989). p53: a frequent target for genetic abnormalities in lung cancer. Science 246, 491–494. Tyldesley, W.R., and Appleton, J. (1973). Observations on the ultrastructure of the epithelium in oral lichen planus. J. Oral. Pathol. 2, 46–57. Uttararvichen, T., Buddhiswasdi, V., and Pairojkul, C. (1996). Bile duct cancer and the liver fluke: pathology, presentation and surgical management. Asian J. Surg. 19, 267–270. Wiseman, H., and Halliwell, B. (1996). Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem. J. 313, 17–29. Wu, X., Takenaka, K., Sonoda, E., Hochegger, H., Kawanishi, S., Kawamoto, T., Takeda, S., and Yamazoe, M. (2006). Critical roles for polymerase z in cellular tolerance to nitric oxideinduced DNA damage. Cancer Res. 66, 748–754. Yermilov, V., Rubio, J., Becchi, M., Friesen, M.D., Pignatelli, B., and Ohshima, H. (1995). Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro. Carcinogenesis 16, 2045–2050. Zaki, M.H., Akuta, T., and Akaike, T. (2005). Nitric oxide-induced nitrative stress involved in microbial pathogenesis. J. Pharmacol. Sci. 98, 117–129.