Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

Abstract

Recently, it was proposed that inflammation plays an integral role in the development of human papilloma virus (HPV)-induced cervical cancer. The present study sought to examine if 8-nitroguanine, a mutagenic nitrative DNA lesion formed during inflammation, contributes to cervical carcinogenesis. We obtained biopsy specimens from 30 patients with cervical intraepithelial neoplasia (CIN)1 (n = 9), CIN2 (n = 10), CIN3 (n = 6) and condyloma acuminatum (n = 5). We used immunohistochemistry to detect the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2′ ′ ′ ′-deoxyguanosine (8-oxodG), an oxidative DNA lesion, and compared it with the expression of the cyclindependent kinase inhibitor p16, which is considered to be a biomarker for cervical neoplasia. Double immunofluorescence labeling revealed that 8-nitroguanine and 8-oxodG were colocalized in cervical epithelial cells. Samples from CIN2-3 patients, most of whom were infected with high-risk HPV subtypes, exhibited significantly more intense staining for 8-nitroguanine than those with condyloma acuminatum. 8-Nitroguanine and 8-oxodG immunoreactivities correlated significantly with the CIN grade. We observed the expression of inducible nitric oxide synthase in epithelial and inflammatory cells from CIN lesions. Proliferating cell nuclear antigen was expressed specifically in dysplastic epithelial cells, but not in those of condyloma acuminatum. There were no statistically significant differences in p16 expression between CIN and condyloma acuminatum samples. These results suggest that high-risk HPV types promote inducible nitric oxide synthase-dependent DNA damage, which leads to dysplastic changes and carcinogenesis; in contrast, p16 appears to be merely a marker of HPV infection. Thus, 8-nitroguanine is a more suitable and promising biomarker for evaluating the risk of inflammation-mediated cervical carcinogenesis than p16. (Cancer Sci 2007; 98: 964-972) C ervical cancer is the second most common cancer among women worldwide, being the most common cancer among women in many regions of developing countries.(1) Molecular epidemiological studies have demonstrated that specific subtypes of HPV are associated with cervical cancer.(2-7) HPV DNA is detectable in greater than 90% of patients with cervical cancer. (3,5,7) The International Agency for Research on Cancer has determined that HPV-16 and HPV-18 are carcinogenic to humans (group 1) and that some other types of HPV are probably or possibly carcinogenic.(2) HPV infection is a necessary event preceding the development of premalignant lesions in the cervical epithelium, referred to as CIN or dysplasia, which can partially progress to cancer.(8) The mechanisms of HPV-induced cervical carcinogenesis, however, are not fully understood. Recently, the chronic inflammation induced by infection has been suggested as an important risk factor of various cancers.(9) Epidemiological studies have revealed that cervical inflammation in women infected with HPV is associated with cervical neoplasia, (8,10) although it is still unc...

FAT10 mediates the effect of TNF-α in inducing chromosomal instability

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Role of Chronic Inflammation and Resulting DNA Damage in Cervical Carcinogenesis Induced by Human Papillomavirus

“…We have demonstrated that inflammation-mediated DNA lesions were formed in cervical tissues of CIN patients (Hiraku et al, 2007). To date, no evidence suggesting that HPV infection alone induces inflammatory states has been provided.…”

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

“…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 [52]. Inflammation-mediated DNA damage, which precedes the genomic abnormalities caused by HPV oncoproteins, may play an important role in carcinogenesis.…”