Mesothelioma, an aggressive malignancy associated with occupational exposure to asbestos and more recently linked to Simian Virus 40 (SV40) is a fatal tumor resistant to therapy. The incidence of mesothelioma is predicted to rise in the next decades, creating a pressing need for new therapeutic strategies. Efforts to elucidate the molecular events that drive tumor promotion and progression in mesothelioma have revealed a relationship between Activator Protein-1 (AP-1), increased expression of Fra-1 in AP-1 complexes and morphologic transformation of mesothelial cells. Pathogenic fibers, including certain families of asbestos fibers and/or SV40, activate the mitogen-activated protein kinase (MAPK) cascade; an event that precedes increases in steady-state mRNA levels of AP-1 (fos/jun) family members. The study of the molecular events that lead to Fra-1 expression, and the discovery of target genes of Fra-1 is a novel approach to establish possible molecular targets for mesothelioma treatment and to establish the role of these molecular events in carcinogenesis. In this proposal, it is hypothesized that asbestos and/or SV40-induced Fra-1 and expression of target genes is linked to mesothelial cell proliferation, transformation and malignancy.
In Specific Aim 1, genes involved in tumorigenesis that are regulated by Fra-1 will be determined in human mesotheliomas using microarray techniques.
In Specific Aim 2, novel Fra-1 target promoters will be assessed in human mesothelioma cells by chromatin immunoprecipitation techniques.
In Specific Aim 3, the effect of modulating Fra-1 and selected genes in proliferation, morphological transformation and tumorigenesis will be studied in normal and asbestos-exposed isolated rat mesothelial (RPM) cells, a mesothelial cell line isolated from a rat chronically exposed to asbestos in vivo and rat and human mesothelioma cells. This proposal will provide the basis for the candidate's training and career in cancer research. It will also provide information on the role of Fra-1 in functional outcomes linked to fiber- and SV40-induced carcinogenesis, allowing future development of possible therapeutic strategies in mesothelioma. The long-term goal of this research plan is to understand the molecular mechanisms governing mesothelial cell tumorigenesis.
