| Popis: |
Viruses are the etiological agents of approximately 12% of human cancers. However, only a subset of viral infections eventually progress to cancer. As obligate intracellular parasites, viruses create a host-cell environment that is amenable to virus replication. These changes to host-cell processes during infection are enacted by virally-encoded proteins that act as molecular hubs. When these processes intersect with pathways that encourage the development of cancer, such as the p53 tumour suppressor pathway, these virally-encoded molecular hub proteins function as viral oncoproteins. One major requirement of both virus infected cells and rapidly growing cancer cells is an altered metabolism that provides the rapid production of energy and macromolecules required for either viral or cellular replication. Typically, this metabolic phenotype involves an increased rate of glycolysis and a decreased rate of cellular respiration despite the presence of ample oxygen that would otherwise encourage respiration. The purpose of this thesis is to investigate how viruses belonging to a subset viruses known as DNA tumour viruses can reprogram cellular metabolism. We hypothesize that DNA tumour viruses cause a cancer-like metabolic phenotype in the infected cell or cancerous tissue, which is similar to, but still distinct from, the metabolic phenotype in corresponding non-virally induced cancers. First, we determined that the 13S isoform of the E1A oncoprotein found in human adenovirus is responsible for causing an increase in glycolysis both as an endogenously expressed protein and in HAdV infected cells. Next, we utilized The Cancer Genome Atlas, a repository of patient tumour data, to determine that human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) have a distinct metabolism-related transcriptome when compared to HPV- HNSCC, and that some of these metabolic genes are associated with patient survival. Finally, we confirm that DNA tumour virus-induced cancers do have a distinct metabolism-related transcriptome in the context of another cancer, Epstein-Barr virus associated gastric cancer. These findings highlight that the metabolic phenotypes of virally infected cells and cancer cells, while superficially similar, are distinct enough to represent potential novel druggable targets or biomarkers. |
