Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Mechanisms of TGFß1 signaling and repression of E-cadherin in Oral Cancer (#114)

Ali Nawshad 1 , Azadeh Jalali , ChangChih Liu
  1. College Of Dentistry, Lincoln, NE, United States
Epithelial Mesenchymal Transitions (EMT) creates invasive cell types from relatively sedentary epithelial cells during embryogenesis, carcinoma invasiveness, and metastasis. The primary traits of mesenchymal cells are cell motility, migration and invasion into the extra cellular matrix. Transforming Growth Factor ß1 (TGF1) is a potent inducer of EMT in cancer metastasis.  Cell-cell adhesion molecule, E-cadherin acts as powerful tumor suppressors in all epithelia. Loss of E-cadherin, facilitates cell migration and invasion, and is a hallmark of EMT. TGFß1 is known to cause loss of cell-cell adhesion and loss of cell polarity during metastasis of Oral Squamous Cell Carcinomas (OSCC). But the molecular mechanisms that control the onset of EMT by repressing E-cadherin remain largely unexplored. Objectives: We proposed to investigate the mechanisms of transcriptional down regulation of E-cadherin in response to TGFß1 signaling. Methods: We used cells derived from OSCC (UMSSC-38) and treated them with exogenous recombinant TGFß1 to evaluate cellular response and EMT. We dissected the TGFß1 pathways in detail to demonstrate the activation of kinases and transcription factors downstream to TGFß1 to show the mechanisms of TGFß1 signaling during OSCC EMT. Results: We have demonstrated that TGFß1 signals via both Smad dependent and Smad independent pathways to activate several EMT related transcription factors such as, Snail and SIP1. All these transcription factors directly downregulate E-cadherin gene activity and thereby repress cell-cell adhesion. Our results also showed that TGFß1 signaling promotes acquisition of mesenchymal markers such as Fibronectin and Vimentin to facilitate cell migration and invasion of UMSCC-38 cells. Conclusion: Our results define the pathways of TGFß1 that alters E-cadherin affecting cellular motility, invasiveness in OSCC. Collectively, our results suggest that combinatorial detection of these proteins could serve as a new tool for EMT analysis in oral cancer patients.