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.
| Chavez, Miquella G; Buhr, Christian A; Petrie, Whitney K et al. (2012) Differential downregulation of e-cadherin and desmoglein by epidermal growth factor. Dermatol Res Pract 2012:309587 |
| Shirley, Stephanie H; Hudson, Laurie G; He, Jing et al. (2010) The skinny on Slug. Mol Carcinog 49:851-61 |
| Hudson, Laurie G; Gale, James M; Padilla, R Steven et al. (2010) Microarray analysis of cutaneous squamous cell carcinomas reveals enhanced expression of epidermal differentiation complex genes. Mol Carcinog 49:619-29 |
| Kusewitt, Donna F; Choi, Changsun; Newkirk, Kimberly M et al. (2009) Slug/Snai2 is a downstream mediator of epidermal growth factor receptor-stimulated reepithelialization. J Invest Dermatol 129:491-5 |
| Newkirk, Kimberly M; Duncan, F Jason; Brannick, Erin M et al. (2008) The acute cutaneous inflammatory response is attenuated in Slug-knockout mice. Lab Invest 88:831-41 |
| Newkirk, Kimberly M; MacKenzie, Debra A; Bakaletz, Alan P et al. (2008) Microarray analysis demonstrates a role for Slug in epidermal homeostasis. J Invest Dermatol 128:361-9 |
| Newkirk, Kimberly M; Parent, Allison E; Fossey, Stacey L et al. (2007) Snai2 expression enhances ultraviolet radiation-induced skin carcinogenesis. Am J Pathol 171:1629-39 |
| Hudson, Laurie G; Choi, Changsun; Newkirk, Kimberly M et al. (2007) Ultraviolet radiation stimulates expression of Snail family transcription factors in keratinocytes. Mol Carcinog 46:257-68 |
| Vanbuskirk, Anne; Oberyszyn, Tatiana M; Kusewitt, Donna F (2005) Depletion of CD8+ or CD4+ lymphocytes enhances susceptibility to transplantable ultraviolet radiation-induced skin tumours. Anticancer Res 25:1963-7 |
| Savagner, Pierre; Kusewitt, Donna F; Carver, Ethan A et al. (2005) Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes. J Cell Physiol 202:858-66 |
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