Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells
© The Author(s) 2016
Received: 2 April 2016
Accepted: 27 July 2016
Published: 1 January 2017
Infection and chronic inflammation have been recognized as important factors for carcinogenesis. Under inflammatory conditions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from inflammatory and epithelial cells, and result in the formation of oxidative and nitrative DNA lesions, such as 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) and 8-nitroguanine. The DNA damage can cause mutations and has been implicated in inflammation-mediated carcinogenesis. It has been estimated that various infectious agents are carcinogenic to humans (IARC group 1), including bacterium Helicobacter pylori (H. pylori), viruses [hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV) and Epstein-Barr virus (EBV)] and parasites [Schistosoma haematobium (SH) and Opisthorchis viverrini (OV)]. H. pylori, HBV/HCV, HPV, EBV, SH and OV are important risk factors for gastric cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, bladder cancer, and cholangiocarcinoma, respectively. We demonstrated that 8-nitroguanine was strongly formed via inducible nitric oxide synthase (iNOS) expression at these cancer sites of patients. Moreover, 8-nitroguanine was formed in Oct3/4-positive stem cells in SH-associated bladder cancer tissues, and in Oct3/4- and CD133-positive stem cells in OV-associated cholangiocarcinoma tissues. Therefore, it is considered that nitrative and oxidative DNA damage in stem cells may play a key role in infection-related carcinogenesis via chronic inflammation.
Keywords8-OHdG 8-oxodG 8-nitroguanine Oxidative stress Inflammation
Human cancer caused by infectious agents worldwide and possible markers
Number of cancer cases
Cancer cases world wide (%)
Detection of 8-nitroguanine [Refs.]
Possible markers for CSC 
SALL4, KLF5, LgR5
Cervix and other sites
Patients with HCV 
Mice with HBV [Fig. 5B, unpublished data]
Oct3/4 (patients with SH) 
CD44v6 (patients without SH) 
CD133, Oct3/4 
Total infection- related cancers
Total cancers in 1995
DNA damage in inflammation-related carcinogenesis
Under inflammatory conditions, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from inflammatory and epithelial cells. ROS and RNS are capable of causing damage to various cellular constituents, such as nucleic acids, proteins and lipids. ROS are generated from multiple sources, including inflammatory cells, carcinogenic chemicals and their metabolites, and the electron transport chain in mitochondria [2, 3]. ROS can induce the formation of oxidative DNA lesion products, including 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG), which is considered to be mutagenic .
Nitric oxide (NO) is synthesized by NO synthases. There are three isoforms, neuronal NO synthase (nNOS, also known as NOS1), inducible NO synthase (iNOS or NOS2) and endothelial NO synthase (eNOS or NOS3) [9, 10]. iNOS is activated to drastically generate NO in inflammatory and epithelial cells under inflammatory conditions, while eNOS and nNOS are constitutively expressed and produce relatively small amounts of NO. iNOS can be also up-regulated by transcription factors such as NF-kB, HIF-1α, STAT, tumor necrosis factor-α (TNF-α). NF-kB plays a central role in inflammation through its ability to induce transcription of proinflammatory genes, including iNOS, and functions as a tumor promoter in inflammation-associated cancer .
8-Nitroguanine is considered to be not only a marker of inflammation, but also a potential mutagenic DNA lesion involved in carcinogenesis . We have investigated the formation of 8-nitroguanine and 8-oxodG in various clinical specimens and animal models in relation to inflammation-related carcinogenesis, as summarized in Table 1. When specimens or cultured cells were pretreated with RNase, 8-nitroguanine was more clearly observed in the nuclei of cells by immunostaining. It suggests that 8-nitroguanine is formed mainly in genomic DNA. It is noteworthy that nitrative and oxidative DNA lesions were specifically induced at cancer sites under chronic infection and various inflammatory conditions, as reviewed previously [2, 3, 20]. We demonstrated that 8-nitroguanine was strongly formed via iNOS expression at related cancer sites of H. pylori, HBV, HCV, HPV, EBV and SH, OV [2, 3, 21, 22]. The IARC classification of CS has been recently updated from 2A to 1, so we have not yet collected enough data for 8-nitroguanine.
Nitrative and oxidative stresses cause DNA damage, contributing to the accumulation of mutations in tissues throughout the carcinogenic process. Particularly, 8-nitroguanine formation may participate in inflammation-related carcinogenesis as a common mechanism. Therefore, 8-nitroguanine could be used as a potential biomarker of inflammation-related carcinogenesis.
Cancer stem cell markers in inflammation-related carcinogenesis
H. pylori infection and gastric cancer
There are several papers concerning the relation of cancer stem cells in H. pylori induced carcinogenesis. H. pylori colonize and manipulate the progenitor and stem cell components, which alters turnover kinetics and glandular hyperplasia . H. pylori infection and inflammation leads to an epithelial-mesenchymal transition (EMT) and altered tissue regeneration and differentiation from both local epithelial stem cells and bone marrow-derived cells (BMDCs) . These abilities to alter the stem cells may be involved in generating cancer stem cells, in addition to mutagenic DNA damage.
HBV or HCV infection and liver cancer
HBV or HCV is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma throughout the world [35, 36]. HBV / HCV may account for about 80 % of hepatocellular carcinoma cases [37, 38]. It is generally accepted that hepatocellular carcinoma arises through a multistep process of genetic alterations in hepatocytes during chronic hepatitis C (CHC). However, the mechanism of HCV infection-induced hepatitis followed by hepatocarcinogenesis via DNA damage is still unclear.
It has been reported that hepatic progenitor cells increase in the liver of HCV patients as the disease advances to cirrhosis, while CD133 (stem/progenitor cell marker) -positive cancer stem cells correlated with early recurrence and poor prognosis among HBV related HCC patients . HBV/HCV modulate hypoxic pathways to adapt cells in hypoxic conditions conferring EMT characteristics . Hypoxia sustains the self-renewal characteristics of a portion of cancer cells in hypoxic niches mainly due to the upregulation of Oct4, NANOG, SOX2, Klf4, and c-myc . It is necessary to study whether 8-nitroguanine forms in cancer stem cells.
Human papillomavirus and cervical cancer
Although it is unclear whether HPV infection alone induces the inflammatory responses, epidemiological studies have suggested that cervical inflammation in HPV-infected women is associated with cervical neoplasia [47, 49]. Co-infection with HPV and other pathogens increase the risk of cervical cancer. Among HPV DNA-positive women, infection with herpes simplex virus-2 is associated with the risk of invasive cervical carcinoma. Molecular epidemiological studies have shown that COX-2 is overexpressed in cervical cancer [50, 51]. These findings suggest that inflammation plays a substantial role in HPV-mediated carcinogenesis.
To clarify the role of inflammation-mediated DNA damage in cervical carcinogenesis, we examined 8-nitroguanine formation in cervical biopsy specimens of patients obtained from HPV-infected patients. We compared the extent of 8-nitroguanine formation in patients with different stages of CIN caused by high-risk HPV and condyloma acuminatum, benign cervical warts caused by low-risk HPV. 8-Nitroguanine was formed in the nuclei of atypical epithelial cells of CIN patients but not in condyloma acuminatum patients. Statistical analysis revealed that the staining intensity of 8-nitroguanine was significantly increased in the order of condyloma acuminatum < CIN1 < CIN2-3 . Inflammation-mediated DNA damage, which precedes the genomic abnormalities caused by HPV oncoproteins, may play an important role in carcinogenesis.
López et al. reviewed human papillomavirus infections and cancer stem cells of tumors from the uterine cervix . Stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 . The stem cell related, cell surface protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer .
Epstein–Barr virus and nasopharyngeal carcinoma
Lymphomas, gastric cancer and nasopharyngeal carcinoma (NPC) are strongly associated with EBV infection, and account for approximately 1 % of cancer cases worldwide . NPC has a profoundly skewed geographical incidence, being common in the arctic (Inuits and Aleuts), North Africa, and South East Asia . The remarkably higher incidence of NPC among the Chinese, especially in South China and South Eastern Asia is mainly attributed to the non-keratinizing subtype, which has a virtually 100 % association with EBV [4, 56].
Recently interesting study has been reported . EBV-encoded LMP1 could induce development of CD44-positive stem-like cells in NPC. LMP1 activated and triggered phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, which subsequently stimulated expression of CD44, development of side population and tumor sphere formation.
DNA damage and mutant stem cells induced by Schistosoma haematobium infection
Chronic infection with SH is associated with urinary bladder cancer, especially in the Middle East and Africa . Contact with contaminated river water is the major risk factor for infection. It is believed that the parasite’s eggs in the host bladder result in irritation, eventual fibrosis and chronic cystitis, leading to carcinogenesis. We demonstrated for the first time that 8-nitroguanine is formed in the tumors of bladder cancer patients with SH infection, by immunohistochemical analysis . The formation of 8-nitroguanine and 8-oxodG was significantly higher in bladder cancer and cystitis tissues than in normal tissues. iNOS expression was co-localized with NF-kB in 8-nitroguanine-positive tumor cells from bladder cancer patients. NF-kB can be activated by TNF-α, a major mediator of inflammation, stimulated by SH egg antigen. These suggest that both 8-nitroguanine and 8-oxodG are formed by iNOS-mediated NO overproduction via NF-kB activation, under SH-caused chronic inflammation.
DNA damage and mutant stem cells induced by OV infection
Chronic infection with the liver flukeOV is associated with cholangiocarcinomas (CCA) . Repeated intake of raw fish containing the infective stage of OV is a cause of the parasite-induced CCA. Re-infection with OV is a major risk factor of CCA in northeast Thailand. We assume that OV-associated CCA is one of a model of inflammation-mediated carcinogenesis. We demonstrated 8-nitroguanine and 8-oxodG formation in the bile duct of hamsters fed with metacercariae of OV [68–70]. These DNA lesions were observed in inflammatory cells and epithelium of bile ducts, and their formation increased in a manner dependent on infection times. The anthelminthic drug praziquantel dramatically diminished the DNA lesions and iNOS expression in OV-infected hamsters. Thus, repeated OV-infection can induce the iNOS-dependent nitrative and oxidative damage to nucleic acids in bile ducts via NF-\( k \)B expression, which may participate in CCA.
In our study with patients, the formation of 8-oxodG and 8-nitroguanine occurred to a much greater extent in cancerous tissues than in non-cancerous tissues in CCA patients, indicating that these DNA lesions contribute to tumor initiation . Urinary 8-oxodG levels were significantly higher in CCA patients than in OV–infected patients, and higher in OV–infected subjects than in healthy subjects. The urinary 8-oxodG levels in OV–infected patients significantly decreased two months after praziquantel treatment .
Our study with proteomics approach showed that oxidation of serotransferrin, alpha-1-antitrypsin (A1AT) and heat shock protein 70-kDa protein 1 (HSP70.1) were significantly associated with poor prognoses . HSP70.1 acts as a molecular chaperone to protect various cells from oxidative stress. A1AT, a glycoprotein, is a member of the serpins (serine protease inhibitors), inhibitors of a wide variety of proteases in relation to tumor invasion. Serotransferrin (transferrin) is an iron (Fe3+)-binding and -transporting protein. Interestingly, we observed that serotransferrin was highly expressed and co-localized with iron in the tumor, suggesting iron accumulation and its release from oxidatively-damaged serotransferrin. We have proposed that oxidative damage of serotransferrin, HSP70.1 and A1AT may induce oxidative stress by iron-accumulation and dysfunction of anti-oxidative and anti-invasive properties, leading to increased oxidative DNA damage and progression of CCA.
Nitrative and oxidative DNA lesions with mutagenic properties are formed in various types of inflammation-related cancer tissues. We have proposed a mechanism for the generation of cancer stem cells by inflammation in Fig. 2. Chronic inflammation by infectious agents, inflammatory diseases, and other factors causes various types of damage to nucleic acids, proteins, tissue and so on, via ROS/RNS generation. Tissue injury under chronic inflammation may activate progenitor/stem cells for regeneration. In these cells, ROS/RNS from inflammation can cause multiple mutations, which may generate mutant stem cells and cancer stem cells, leading to carcinogenesis. Indeed, 8-nitroguanine was formed in stemness marker-positive cells in parasite-associated cancer tissues. The mechanism for generation of cancer stem cells will be explained by our ongoing studies on the formation of 8-nitroguanine in stem-like cells of target tissues associated with other inflammation-related cancers.
Bone marrow-derived cells
Cytotoxin-associated gene A
Chronic hepatitis C
Cervical intraepithelial neoplasia
Epidermal growth factor receptor
Endothelial NO synthase
- H. pylori :
Hepatitis B virus
Hepatitis C virus
Human immunodeficiency virus-1
Heat shock protein 70-kDa protein 1
Human T-cell lymphotropic virus type 1
International Agency for Research on Cancer
Inducible NO synthase
Latent membrane protein 1
Mucosa-associated lymphoid tissue
Microtubule affinity-regulating kinase
Neuronal NO synthase
Nucleotide-binding oligomerization domain protein 1
- O2 − :
- ONOO− :
Phosphoinositide 3-kinase/protein kinase B
Reactive nitrogen species
Reactive oxygen species
Src homology 2 domain-containing phosphatase 2
Signal transducer and activator of transcription-3
Tumor necrosis factor-α
SK is funded by Grant-in-Aid for Scientific Research (C) (15 K08787), Japan Society for the Promotion of Science (JSPS), The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. SO is funded by Grant-in-Aid for Scientific Research (C) (26460813), Japan Society for the Promotion of Science (JSPS), The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. No conflict of interest statement is declared.
This work was partly supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant Numbers 15 K08787, 26460813).
Availability of data and materials
This review does not include new relevant raw data. We removed identifying information from all tissue samples. See, references for original data; H. pylori , HPV , HBV/HCV , EBV , SH [21, 22], OV [71, 74, 75].
SK conceived of the design of the study. All authors participated to draft, read and approve the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
Studies in this review have been performed in accordance with the Declaration of Helsinki and approved by appropriate ethics committees. All animal experiments except for OV infection were carried out according to the protocol approved by the Ethics Committee for Animal Experiments at Mie University School of Medicine. See references for details; H. pylori , HPV , HBV/HCV , EBV , SH [21, 22], OV [71, 74, 75].
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