Modulators of EMT in Skin Carcinogenesis

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): Epithelial-mesenchymal transformation (EMT) is a dramatic shift in cell morphology that occurs during development, wound repair, and carcinoma progression. EMT is characterized by conversion of anchored epithelial cells expressing cytokeratin into migratory fibroblast-like cells that express vimentin. The process of EMT requires loss of cell:cell adhesion mediated by desmosomes and increased secretion of extracellular matrix-degrading proteases. Responses remarkably similar to EMT take place in keratinocytes in response to epidermal growth factor receptor (EGFR) activation or ultraviolet radiation (UVR) exposure. Based on this similarity and on our own finding that UVR or EGFR activation by endogenous ligands induces Slug, a putative transcription factor that modulates EMT during development and is implicated in disruption of desmosomes in adult epithelium, we hypothesize that elevated Slug plays an important role in the EMT occurring during the progression of UFR-induced squamous cell carcinomas (SCCs) to aggressively invasive and metastatic tumors. Our preliminary studies demonstrate that 1) both EGF and UVR enhance Slug mRNA expression in cultured human keratinocytes, 2) UVR-dependent modulation of Slug expression is mediated, at least in part, through activation of the EGFR, 3) Slug expression is enhanced during the EMT that occurs as part of wound healing, and 4) constitutive expression of exogenous Slug in keratinocytes enhances cell dispersion and accelerates wound healing. These findings suggest that Slug induction represents a point of convergence for diverse extracellular signals that stimulate EMT. Because EMT is recapitulated during SCC progression, it is important to understand the molecular regulators of the process. Our studies in genetically modified mice will quantitatively evaluate changes in Slug expression during UVR carcinogenesis, determine the consequences for UVR carcinogenesis of enhancing or abrogating Slug expression, and clarify the role of EGFR activation in UVR induction of Slug during skin carcinogenesis. In addition, we will quantify Slug expression in human SCCs and analyze the patterns of gene expression associated with enhanced Slug expression in human keratinocytes. The fundamental knowledge about the biology of SCC that we gain will be important in designing preventive and therapeutic strategies to address the increasing incidence of SCC in the general population and will be particularly valuable for dealing with the greatly increased risk for SCC and the accelerated SCC progression that are observed in immunosuppressed transplant recipients and AIDS patients.