Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection. 2007

Yusuke Hiraku, and Tsutomu Tabata, and Ning Ma, and Mariko Murata, and Xiaohui Ding, and Shosuke Kawanishi
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie, Japan.

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.

UI MeSH Term Description Entries
D007150 Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Immunocytochemistry,Immunogold Techniques,Immunogold-Silver Techniques,Immunohistocytochemistry,Immunolabeling Techniques,Immunogold Technics,Immunogold-Silver Technics,Immunolabeling Technics,Immunogold Silver Technics,Immunogold Silver Techniques,Immunogold Technic,Immunogold Technique,Immunogold-Silver Technic,Immunogold-Silver Technique,Immunolabeling Technic,Immunolabeling Technique,Technic, Immunogold,Technic, Immunogold-Silver,Technic, Immunolabeling,Technics, Immunogold,Technics, Immunogold-Silver,Technics, Immunolabeling,Technique, Immunogold,Technique, Immunogold-Silver,Technique, Immunolabeling,Techniques, Immunogold,Techniques, Immunogold-Silver,Techniques, Immunolabeling
D009604 Nitrosoguanidines Nitrosylated derivatives of guanidine. They are used as MUTAGENS in MOLECULAR BIOLOGY research.
D002575 Uterine Cervicitis Inflammation of the UTERINE CERVIX. Cervicitis,Cervicitides,Cervicitides, Uterine,Cervicitis, Uterine,Uterine Cervicitides
D002578 Uterine Cervical Dysplasia Abnormal development of immature squamous EPITHELIAL CELLS of the UTERINE CERVIX, a term used to describe premalignant cytological changes in the cervical EPITHELIUM. These atypical cells do not penetrate the epithelial BASEMENT MEMBRANE. Cervical Dysplasia,Cervical Intraepithelial Neoplasia,Cervix Dysplasia,Dysplasia of Cervix Uteri,Neoplasia, Cervical Intraepithelial,Cervical Intraepithelial Neoplasia, Grade III,Cervical Intraepithelial Neoplasms,Intraepithelial Neoplasia, Cervical,Cervical Dysplasia, Uterine,Cervical Dysplasias,Cervical Intraepithelial Neoplasm,Cervix Uteri Dysplasia,Cervix Uteri Dysplasias,Dysplasia, Cervical,Dysplasia, Cervix,Dysplasia, Uterine Cervical,Intraepithelial Neoplasm, Cervical,Intraepithelial Neoplasms, Cervical,Neoplasm, Cervical Intraepithelial,Neoplasms, Cervical Intraepithelial
D003218 Condylomata Acuminata Sexually transmitted form of anogenital warty growth caused by the human papillomaviruses. Genital Warts,Venereal Warts,Warts, Genital,Warts, Venereal,Genital Wart,Venereal Wart,Wart, Genital,Wart, Venereal
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D030361 Papillomavirus Infections Neoplasms of the skin and mucous membranes caused by papillomaviruses. They are usually benign but some have a high risk for malignant progression. HPV Infection,Human Papillomavirus Infection,HPV Infections,Human Papillomavirus Infections,Papillomavirus Infection,Papillomavirus Infection, Human,Papillomavirus Infections, Human

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