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Malignant mesothelioma (MM), an aggressive malignancy associated with exposures to asbestos, and more recently implicated with Simian Virus 40 (SV40) infection, is a fatal tumor resistant to conventional therapies. The incidence of MM is increasing, creating a pressing need for new therapeutic strategies. Our research has linked activation of the Extracellular Signal Regulated Kinase (ERK1/2) cascade of the Mitogen Activated Protein Kinase (MAPK) pathways to fra-1 transactivation and morphological transformation of mesothelial cells. Recently, we have also discovered that asbestos activates ERK5, a redox-sensitive MAPK pathway that is linked to chemoresistance. In this project, we will determine the roles of ERK1/2 and ERK5 in proliferation/survival and tumorigenesis of human mesothelial cells and mesotheliomas. We hypothesize that ERK1/2 and ERK5 contribute uniquely to the expression of early response protooncogenes (fos/jun family members) as well as other genes critical to cell proliferation/survival, transformation, and tumor growth of MM. In Aim #1, the contributions of ERK1/2 and ERK5 to activator protein-1 (AP-1) transactivation, markers of proliferation/survival, and altered gene expression by asbestos and SV40, alone and in combination, will be examined in human mesothelial cells using small hairpin RNA interference (RNAi) approaches (shMEK1/2, shERK5). In Aim #2, the functional effects and changes in gene expression by silencing ERK1/2 and ERK5 pathways alone and in combination will be revealed in SV40 T-antigen (Tag) positive and negative human MM cells in vitro. In Aim #3, a mouse orthotopic model will be used to assess modifications in human MM development intrapleurally after silencing of ERK1/2 and ERK5 alone and in combination. Research will provide information on ERK pathways governing mesothelial cell transformation and tumor development, providing support for new therapeutic strategies for MM. Our research team consists of an expert in mechanisms of asbestos carcinogenesis (Dr. Mossman), experts in microarray and RNAi approaches (Drs. Ramos-Nino and Chaudry), a biostatistician (Dr. Vacek), a leader in Bioinformatics (Dr. Bond), a chemist who has designed amorphous particles (APMS) for efficient delivery of constructs (Dr. Landry), a pathologist with expertise in mouse orthotopic models in cancer research (Dr. Bosenberg), and a pathologist exploring mechanisms of SV40-induced mesotheliomas (Dr. Carbone).
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