Regulation of tumorigenesis by alternative pre-mRNA splicing

Duke University, Durham NC

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Abstract

DESCRIPTION (provided by applicant): Epithelial plasticity, the ability of cells to transition between epithelial and mesenchymal states, is required for epithelial cancers, including prostate cancer (PC), to metastasize. One of the many changes that occur in response to epithelial plasticity is the alternative pre-mRNA splicing (AS) of cellular transcripts. AS is a major regulatr of mammalian gene expression, and is also involved in cancer cell proliferation, apoptosis and invasiveness. Therefore, it is likely that prostate tumor progression correlates with, or may even be caused by, changes in the regulation of AS. The goal of this research is to characterize the role of epithelial-specific splicing in epithelial plasticity and prostate tumorigenesis using fluorescent AS reporters [in vitro and in vivo in whole animal models, and to validate these findings in human PC patient samples]. Because the microenvironments that are unique to a cell or tissue can alter the AS of transcripts, the use of fluorescent AS reporters allows for the n situ visualization of mRNA splicing decisions made by individual cells. In the proposed experiments, AS factors and a transcription factor that are associated with epithelial plasticity will be expressed in epithelial cells that have been artificially induced to undergo EMT and become mesenchymal. The ability of these cells to alternatively splice the fluorescent mRNA reporters in response to changes in epithelial plasticity will be visualized in cell culture and ina whole animal model of prostate tumor progression. [Human PC samples will also be interrogated for the expression of AS factors, and a transcription factor, that are involved in epithelial plasticity. Ultimately, I will validate the findings from the in vitro and in vivo experiments in human patient samples,] and will validate the biological significance between AS, epithelial plasticity, and human prostate tumorigenesis. PUBLIC HEALTH RELEVANCE: Careful study of the regulation of gene expression in a mouse cancer model may advance our understanding of how gene expression is altered during tumorigenesis and metastasis. This investigation may identify novel biomarkers and therapeutic targets important for the early detection and treatment of prostate cancer, respectively.