title: 8-Nitroguanine as a potential biomarker for progression of malignant fibrous histiocytoma, a model of inflammation-related cancer.
abstract: Chronic inflammation is a critical component of carcinogenesis and tumor progression. Reactive nitrogen and oxygen species generated by inflammatory cells form mutagenic DNA lesions, such as 8-nitroguanine, which may play an integral role in inflammation-related carcinogenesis. Hypoxia-inducible factor (HIF)-1alpha has been established as a prognostic biomarker in various tumors, including malignant fibrous histiocytoma (MFH). The aim of this study was to evaluate the impact of 8-nitroguanine formation and HIF-1alpha expression on the prognosis of patients with inflammation-related cancer. Immunohistochemical analyses were employed to examine the distribution of 8-nitroguanine and HIF-1alpha, using clinical specimens from 36 patients with MFH as a model of inflammation-related cancer. 8-Nitroguanine formation was predominantly observed in the nuclei of tumor cells and inflammatory cells in tumor tissues, while HIF-1alpha was expressed in the cytoplasm and nuclei of tumor cells. Little or no immunoreactivity of 8-nitroguanine and HIF-1alpha was observed in adjacent non-tumor tissues. Significantly higher levels of both 8-nitroguanine and HIF-1alpha were observed in the tissue specimens of deceased patients than in those of living subjects. Survival curves analyzed by the Kaplan-Meier method differed significantly between the high- and low-staining groups of 8-nitroguanine (p=0.00003) as well as HIF-1alpha (p=0.01104). These results suggest a significant role of the pathway of iNOS-dependent 8-nitroguanine formation via HIF-1alpha and NF-kappaB on the progression of inflammation-related cancer. In conclusion, 8-nitroguanine is an excellent candidate prognostic and predictive biomarker together with HIF-1alpha in inflammation-related tumor progression.
authors.affiliation: Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hoki
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumine
authors.forename: Atsumasa
authors.initials: A
authors.lastname: Uchida
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D051677:Histiocytoma, Malignant Fibrous / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation; D018836:Inflammation Mediators; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate
chemical_list: C095838:8-nitroguanine; D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D016328:NF-kappa B; D006147:Guanine