MECHANISMS OF FIBER CARCINOGENESIS: FROM MITOCHONDRIAL DAMAGE TO SILENCING OF THE BIGH3 GENE

Although asbestos is a well established human carcinogen, the underlying mechanisms of fiber carcinogenesis are not known. For decades, asbestos has been considered a non-genotoxic carcinogen. Using a mutagenic assay system that is efficient in detecting multilocus deletions, we showed previously that chrysotile is indeed a potent gene and chromosomal mutagen. Furthermore, phagocytosis of asbestos by target cells and the resultant oxyradical production are important mechanistic factors in fiber mutagenesis. To demonstrate that extranuclear target may play a functional role in mediating fiber mutagenesis, enucleated cytoplasts were shown to induce oxyradicals in response to fiber treatment. Furthermore, fiber-treated cytoplasts, upon fusion with non-treated karyoplasts showed a three-fold increase in 8-hydroxyl-deoxyguanosine, a biomarker for oxidative DNA damage. Furthermore, asbestos-treated human bronchial epithelial cells showed alterations in mitochondrial functions including a decrease in cytochrome c oxidase activity, an increase in citrate synthase activity and a decrease in overall oxygen consumption. These alterations correlated with depletion in mtDNA copy number and an increase in large heteroplasmic mtDNA deletions. Using an immortalized human bronchial cell model, we have shown that chrysotile fibers induce step-wise neoplastic transformation of these cells that form progressive growing tumors when inoculated into nude mice. Microarray analyses have identified that the βigH3 gene is consistently under-regulated in tumorigenic cells. Re-expressions of the βigH3 gene in human mesotheliomas that show little or no expression of the gene can revert their tumorigenic phenotypes. These results provide collaborating evidence that chromosomal deletions and loss of tumor suppressor gene functions are crucial events in fiber carcinogenesis.