Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells

Abstract

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.

Keywords: 8-OHdG; 8-nitroguanine; 8-oxodG; Inflammation; Oxidative stress.

Fig. 1

Proposed mechanism of mutation mediated by 8-nitroguanine formation

Fig. 2

Possible mechanism for generating mutant stem cells by inflammation

Fig. 3

Mechanism of carcinogenesis induced by H. pylori infection

Fig. 4

8-Nitroguanine and 8-oxodG formation in gastritis patients with H. pylori infection. Double immunofluorescence staining of paraffin sections shows the localization of 8-nitroguanine (red) and 8-oxodG (green) in the gastric epithelium. Yellow colour in right panels (Merge) shows co-localization of 8-nitroguanine and 8-oxodG

Fig. 5

Left: 8-Nitroguanine and 8-oxodG accumulation in liver tissues from patients [39]. Right: 8-Nitroguanine accumulation and iNOS expression in liver tissues from mice (unpublished data)

Fig. 6

Development of HPV-induced cervical cancer

Fig. 7

Possible mechanisms of HPV-induced cervical carcinogenesis

Fig. 8

Proposed mechanism of EBV-induced carcinogenesis

Fig. 9

Formation of 8-nitroguanine and expression of Oct3/4 in bladder tissues. The formation of 8-nitroguanine (red) and the expression of Oct3/4 (green) were assessed by double immunofluorescence staining [21]. In the merged image, co-localization of 8-nitroguanine and Oct3/4 is indicated in yellow. Biopsy and surgical specimens were obtained from normal subjects and patients with SH-induced cystitis and bladder cancer. Normal tissues and urinary bladder cancer tissues without SH-infection were obtained from a commercial urinary bladder tissue array (Biomax.us, USA)

Fig. 10

Colocalization of stem cell markers and DNA damage. Double-immunofluorescence staining of stem/progenitor cell markers (CD133 and OV6) and DNA lesions (8-oxodG and 8-nitroguanine) in cholangiocarcinoma tissues. White arrows indicate co-localization of DNA damage marker and stemness marker in cancer cells. Original magnification is × 400; Scale bar = 25 μm