This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cell-cell adhesion determines the polarity of cells and participates in the maintenance of the cell societies called tissues. Cell-cell adhesiveness is generally reduced thus allowing cellular migration following an epithelial-to-mesenchymal transition (EMT), a process that occurs in normal developmental processes as well as in human cancers. As a consequence, epithelial cancer cells often lose the morphological hallmarks of typical epithelia as they become invasive and metastatic. Similar modifications of cell-cell interactions are observed duing tumor progression of most carcinomas and has been related to the induction of EMT. We have recently identified a novel pathway where Transforming Growth Factor (TGF)-Beta signals via Smads to activate Lymphoid Enhancing Factor (LEF)-1 to repress E-cadherin expression, thus allowing EMT during mouse embryogenesis. Interestingly, TGF-Beta and Smads have already been implicated during Head and Neck Squamous Cell Carcinoma (HNSCC); however, the mechanisms of activation of downstream signaling and the repression of E-cadherin in response to TGF-beta signaling is largely unknown. Our hypothesis is that TGF-beta signaling represses E-cadherin activity via LEF1 transcription factor resulting in loss of adhesion and thus promoting EMT and invasion in HNSCC. Our laboratory is positioned to make significant contributions to our understanding of E-cadherin function and the role this cellular structure plays in the development of HNSCC.
The specific aims are; (1) to determine if TGF-beta represses E-cadherin expression and thereby influences cell adhesion, proliferation and motility in HNSCC. (2) To further study the mechanism of repression of the E-cadherin promoter in response to TGF-beta signaling and activation of the Smad and LEF1 transcription factors during tumorigenesis, and (3) to determine if TGF-beta signaling promotes acquisition of mesenchymal markers such as fibronectin and vimentin in HNSCC. We will use structure/function studies to investigate the mechanism of TGF-beta signaling, the activation of the Smads and LEF1, and investigate the role of this unique pathway in repressing E-cadherin gene activity. Collectively, the studies proposed herein will define the contribution of a novel signaling patway of TGF-beta and its affect on E-cadherin components for cellular motility, invasiveness in HNSCC.
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