8-Nitroguanine as a potential biomarker for progression of malignant fibrous histiocytoma, a model of inflammation-related cancer.

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.