Abstract 3326: ΔNp63α is a regulator of epithelial-mesenchymal transition in human keratinocytes

Abstract

Abstract p63 is a p53 family protein required for morphogenesis and postnatal regeneration of epithelial tissues. Here we demonstrate that ΔNp63α, a p63 isoform lacking N-terminal transactivation domain, induces epithelial-mesenchymal transition (EMT) in primary human keratinocytes in TGF-β-dependent manner. Rapidly proliferating normal human epidermal keratinocytes (NHEK) were infected with retroviral vector expressing ΔNp63α, ΔNp63α, ΔNp63α, or empty vector, and serially subcultured until replicative senescence. No phenotypic changes were observed until the culture reached senescence. Then, cells transduced with ΔNp63α and ΔNp63α demonostrated morphological changes resembling mesenchymal cells, while ΔNp63α did not trigger such change in phenotype. Treatment with exogenous TGF-β accelerated EMT in pre-senescent ΔNp63α-transduced cells, and inhibition of TGF-β signaling reversed the EMT phenotype. Molecular markers of EMT, such as loss of E-Cadherin and cytokeratin 14 expression, were observed in cells expressing ΔNp63α but not those expressing ΔNp63α. TGF-β treatment alone led to growth arrest in control NHEK with no evidence of EMT, indicating that ΔNp63α altered the cellular response to TGF-β treatment. ΔNp63α-transduced cells acquiring EMT gained ability to be differentiated to osteo/odontogenic and adipogenic pathways, resembling mesenchymal stem cells (MSCs). Furthermore, these cells expressed enhanced levels of Nanog and Lin28, which are transcription factors associated with pluripotency. These data indicate that ΔNp63α triggered EMT in TGF-β-dependent manner, while ΔNp63α only caused morphologically changes resembling mesenchymal cells. The current study suggests that mesenchymal transition of normal skin keratinocytes might be a novel approach to generate induced MSCs (iMSCs), which may be useful for regenerative therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3326. doi:1538-7445.AM2012-3326