EMT Contributes to the Malignant Transformation of Ameloblastoma

Objectives: Ameloblastoma(AB) is a benign but locally aggressive intraosseous epithelial odontogenic tumor. AB is the most common odontogenic tumor in the world, and rarely shows malignant transformation developing ameloblastic carcinoma(AC). AC shows poor prognosis (five-years survival rate: 72%). When metastasis occurs, five-years survival rate decreases to 21%. However, the mechanism of malignant transformation of AB to AC remains unclear. To clarify this problem, DNA micro array analysis was performed in one patient with AB and subsequently occurred AC. Within many upregulated genes, we focused on Zinc finger E-box-binding homeobox 1 (ZEB1) gene, which plays an important role in the epithelial-mesenchymal transition (EMT). In this study, we examined the role of EMT in developing AC from AB.
Methods: DNA micro array and immunohistochemical analyses were performed on the formalin-fixed and paraffin-embedded (FFPE) tissue sections from AB and AC samples. In in vitro experiments, EMT was induced in a human ameloblastoma cell line (AM-1) by TGF-β and EGF stimulation. The AM-1 cells with a high migration activity were selected using a boyden chamber kit, and the expression levels of EMT-related mRNAs and proteins were analyzed.
Results: The expression of ΔNp63, which is an isoform of p63 and suppress EMT in cancer cells, was weaker in AC than in AB by immunohistochemical analyses. In addition, ΔNp63 protein expression was lower in EMT induced AM-1 cells than in control cells. Furthermore, AM-1 cells with a high migration activity showed an upregulation of ZEB1 and a downregulation of ΔNp63 with a statistical significance in mRNA expression and protein analysis, respectively.
Conclusions: EMT induced by upregulation of ZEB1 and downregulation of ΔNp63 contributes to the malignant transformation of AB.