Abstract for presentation at 13th International Congress on Oral Pathology and Medicine

Epithelial-Mesenchymal transformation (EMT), a fundamental mechanism of embryogenesis and tumor progression, is most commonly characterized by loss of the cell adhesion molecule, E-cadherin. During EMT, loss of E-cadherin expression correlates with a transition to front end-back end polarity of invasive metastatic cells. The transformation of Oral Epithelial Squamous Cell Carcinoma Cells (UMSCC) into metastatic phenotype has been well documented. However, signaling mechanisms that promote EMT of UMSCC have not been investigated in detail. Here, we show that Transforming Growth Factor-β (TGFβ) transforms UMSCC cell lines into mesenchymal phenotype. By culturing human UMSCC, we have demonstrated that TGFβ signaling induces EMT by forming activated transcription complexes that directly inhibit E-cadherin gene activity. Our data shows that TGFβ signals via PI3K and ERK to activate Snail transcription factor, which binds with the promoter of the E-cadherin gene. Such DNA-protein interactions repress E-cadherin transcription and gene activity. Subsequently, loss of E-cadherin and cell-cell adhesion allow oral cancer cells to become motile and invasive. Comparing current results with that of our previous data, we speculate that TGFβ signals differently to promote EMT during tumor progression, such as Oral Squamous Cell Carcinoma (when EMT is aggressive and uncontrolled) with that of embryonic EMT (subtle and controlled) as shown by us – J Cell Biol.22;163(6):pp1291-130,2003 and Dev Dyn. 234(1):132-42 2005. These results suggest that TGFβ mediated signaling activates epithelial transformation into migratory metastatic cells by repressing E-cadherin gene activity and it is a potent inducer of oral cancer progression. Supported by CoBRE, NIH.