Initial Characterization of ECOP Overexpression in Squamous Cell Carcinoma of the Upper Aero-digestive Tract

Baras, Alexander S., Department of Pathology, University of Virginia
Moskaluk, Christopher, Department of Pathology, University of Virginia

Squamous cell carcinoma (SCC) is one of the most common histologic types of carcinomas that occur in the aerodigestive tract (oral cavity, larynx, esophagus and the bronchial tree), often as a consequence of exposure to tobacco products. In an effort to identify highly conserved gene expression and genetic changes that may play a functional role in SCC, a cohort ofSCCs was subjected to global gene expression and genetic profiling using Affymetrix U133 and SNP arrays, respectively. These efforts resulted in the identification of EGFR Coamplified and Overexpressed Protein (ECOP), which has been renamed Vesicular Overexpressed in cancer Prosurvival Protein 1 (VOPP1) due to the work presented in this dissertation. The overarching purpose of this dissertation was to examine the relevance of the highly conserved overexpression of ECOP/VOPP1, a fairly novel and uncharacterized protein. Conceptually this was examined from two perspectives: (i) Starting from the gene and protein in a descriptive fashion. (ii) Starting from phenomena associated with this gene in SCC derived cell lines through loss of function studies. In examining the ECOP/VOPP1 protein, it was discovered that it was in fact not a secreted protein, as prior nomenclature had suggested. Rather, it localizes to vesicular structures within the cell ofwhich some exhibited colocalization to perinuclear elements of the lysosomal system. Additionally, ECOP/VOPP1 over-expression in SCC was proven to be independent of and much more common than EGFR amplification, in contrast to the ECOP nomenclature. From II the loss of function analyses, it was clear that ECOP/VOPP1 overexpression does in fact confer a pro-survival phenotype in SCC. Furthermore, the apoptosis observed when ECOP/VOPP1 levels are diminished in SCC is associated with intrinsic apoptotic signaling and is mediated, at least in part, by increased oxidative stress preceding the induction of apoptosis observed. This dissertation has provided new insights with regards to ECOP/VOPP1 and is well suited to guide future endeavors examining this fairly novel protein upregulated in a variety of cancers including SCC, glioblastoma multiforme, breast, and pancreatic adenocarcinomas.

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PHD (Doctor of Philosophy)
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