title: iNOS-dependent DNA damage in patients with malignant fibrous histiocytoma in relation to prognosis.
abstract: Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas. MFH has been proposed to be a lesion accompanied with inflammatory responses. During chronic inflammation, reactive nitrogen and oxygen species generated from inflammatory cells are considered to participate in carcinogenesis by causing DNA damage. 8-nitroguanine is a mutagenic nitrative DNA lesion formed during chronic inflammation. We examined whether nitrative DNA damage is related to the prognosis of MFH patients. We performed immunohistochemical analyses to examine the distribution of DNA damage and the expression of inflammation-related molecules including inducible nitric oxide synthase (iNOS), nuclear factor-kappaB (NF-kappaB), and cyclooxygenase-2 (COX-2) in clinical specimens from 25 patients with MFH. We also analyzed the correlation of DNA damage or the expression of these genes with the prognosis of MFH patients. Immunohistochemical staining revealed that the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), an oxidative DNA lesion, occurred to a much greater extent in MFH tissue specimens from deceased patients than in live patients. iNOS, NF-kappaB and COX-2 were colocalized with 8-nitroguanine in MFH tissues. It is noteworthy that the statistical analysis using the Kaplan-Meier method demonstrated strong 8-nitroguanine staining to be associated with a poor prognosis. In conclusion, 8-nitroguanine appears to participate in not only the initiation and promotion of MFH, but also in the progression of MFH, and could therefore be used as a promising biomarker to evaluate the prognosis of cancer patients.
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: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Akihiko
authors.initials: A
authors.lastname: Matsumine
authors.forename: Masato
authors.initials: M
authors.lastname: Nagahama
authors.forename: Ken
authors.initials: K
authors.lastname: Shintani
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; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D051677:Histiocytoma, Malignant Fibrous / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate
chemical_list: C095838:8-nitroguanine; D018836:Inflammation Mediators; D008565:Membrane Proteins; D016328:NF-kappa B; D006147:Guanine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human