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Ultrastructural and Chromosomal Studies on Manganese Superoxide Dismutase in Malignant Mesothelioma

Department of Medicine, Pulmonary Division, University of Helsinki and Helsinki University Hospital, Helsinki; Departments of Pathology and Medical Genetics, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Laboratory Diagnostics, Helsinki; Departments of Pathology and Internal Medicine, University of Oulu, Biocenter of Oulu, Oulu; and Finnish Institute of Occupational Health, Helsinki, Finland

Address correspondence to: Vuokko Kinnula, Department of Medicine, Pulmonary Division, University of Helsinki and Helsinki University Hospital, Box 22 (Haartmanink 4), 00140 Helsinki, Finland. E-mail: Vuokko.kinnula{at}helsinki.fi

Mesothelioma represents an aggressive tumor type with high resistance to all treatment modalities. Its pathogenesis is strongly associated with exposure to asbestos fibers and probably with free radicals. One of the most important free radical scavenging enzymes, mitochondrial manganese superoxide dismutase (MnSOD), has been shown to be elevated in mesothelioma (K. Kahlos et al., 1998, Am. J. Respir. Cell Mol. Biol. 18:570–580). In the present study, we could detect intense ultrastructural accumulation of MnSOD in the mitochondrial compartment of malignant mesothelioma cells. There was no association between the immunohistochemical reactivity and the most common and functional polymorphic variant of MnSOD, the Ala to Val amino acid change at 9 position (16th amino acid from the beginning of the signal sequence), in the 31 mesothelioma cases investigated. Comparative genomic hybridization and fluorescence in situ hybridization did not reveal any changes in chromosome 6, where the MnSOD gene is located. Sequencing of the MnSOD promoter region in four mesothelioma cell lines showed similar nucleotide variables in the malignant and nonmalignant cells. Therefore, the intense expression of MnSOD in the mitochondria of mesothelioma cells does not appear be associated with any major chromosomal alterations or the polymorphism of MnSOD gene. Association with oxidative/nitrosative stress in mesothelioma using nitrotyrosine immunostaining pointed to a tendency for more intense reactivity in those mesotheliomas with higher MnSOD expression (P = 0.069).

Abbreviations: bovine serum albumin, BSA • comparative genomic hybridization, CGH • fluorescence in situ hybridization, FISH • manganese superoxide dismutase, MnSOD • nuclear factor-B, NF-B • phosphate-buffered saline, PBS • saline sodium citrate, SSC