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
cyclin-dependent 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.