In majority of head and neck squamous cell carcinoma (SCC), chromosomal instability leading to aneuploidy is observed. Approximately 25% of all head and neck SCC have been found to be positive for Human Papillomavirus (HPV), predominantly HPV type 16 (HPV 16). HPV 16 early proteins, E6 and E7, have been shown to be involved in chromosomal instability resulting in polyploidy and aneuploidy, although the mechanism is unclear. In Microarray analysis I carried out to identify genes that are differentially expressed in HPV16 E6/E7 differentiating keratinocytes, a number of genes involved in mitosis and the mitotic checkpoint, were identified as being up or down regulated. Deregulation of any of these genes in the presence of E6 and E7 is likely lead to genomic instability caused by incorrect segregation of chromosomes during mitosis. Therefore, in this proposal, I would like to confirm the identification of a selection of these genes that are regulated by E6 and E7, determine which of the viral genes is involved, and to begin to elucidate the consequences of the over-, or under- expression of these genes for chromosome stability. Chromosome instability occurs very soon after the introduction of E6 and E7 into cells, although importantly, the cells are not transformed, as they do not produce tumors in animals. Therefore, this may help to answer the question of whether chromosome instability is a cause or a result of cellular transformation and malignant conversion. In addition, since chromosomal instability is a common feature of cancers, this work may have broad application. This initial study will facilitate and lead to the development of a RO1 proposal.
| Patel, Daksha; McCance, Dennis J (2010) Compromised spindle assembly checkpoint due to altered expression of Ubch10 and Cdc20 in human papillomavirus type 16 E6- and E7-expressing keratinocytes. J Virol 84:10956-64 |
| Patel, Daksha; Incassati, Angela; Wang, Nancy et al. (2004) Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res 64:1299-306 |
