Abstract
Oral squamous cell carcinoma is highly invasive cancer and this invasion occurs mainly due to the proteolytic activity of metalloproteinases on basal membrane and extracellular matrix. The proteinases are key regulators of both cell-cell and cell-extracellular matrix (ECM) interactions that are associated with all aspects of tumorigenesis and metastasis, and the interest in their potential as targets for the development of anticancer agents dates back many decades. ADAMs, a family of membrane proteinase, have been considered critical in this process due to the high expression in tumors, showing strong correlation with disease progression and development. ADAMs are characterized as sheddases, proteinases that are involved in the regulation of physiological and development processes by the release of surface ectodomain proteins. In addition, there is a triple cross-talk among EGFR, GPCR and ADAMs, and ADAMs function as signaling effectors of GPCR and EGFR, which could determine the regulation of several processes, including cell proliferation and migration. Recently, novel extracellular targets resulting from proteolytic activity of ADAMs have been revealed, indicating that little is known about these molecules considering the vast pathways that could be coordinate by these proteinases. Indeed only a few studies increased knowledge about the ligands and the mechanism they are involved to activate ADAMs. To gain insight into the mechanism of action of ADAM-17, the aim of this project is to elucidate the regulation of ADAM-17 in vitro model of tumorigenic and non-tumorigenic cells, animal model and human tissue using molecular and cellular biology, proteomic and mass spectrometry tools. Different strategies will be performed to modulate ADAM-17 expression to determine novel targets, its cleavage sites, the cytoplasmatic domain ligands, the phosphorylation sites in the cytoplasmatic domain and the phosphorylation sites of membrane proteins. The effect of ADAM-17 modulation in keratinocytes and oral squamous cell carcinoma (CEC) will be evaluated by migration, proliferation, adhesion, invasion and apoptosis assays. To validate and improve the in vitro experiments, the protein and peptide composition will be also evaluated in tumor induced by cell lines with modulated ADAM-17 and in human tissue samples. The gene expression of specific targets will be evaluated in all the models used in this study. The results of this project could improve the knowledge of ligands the signaling pathways of ADAM-17 to elucidate subproteome targets to peptides and inhibitors design that could modulate the ligand binding as well as to reveal potential candidates involved in the initiation and progression of oral cancer, and thus, could aid to the development of novel diagnostic and treatment options for this disease. (AU)
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