Untersperger, CV; (2013) Analysis of Pathways Affected by the Viral Oncogenes in Human Papillomavirus 16-Induced Neoplastic Progression. Doctoral thesis (PhD), UCL (University College London).

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Abstract

While many studies have looked at the role of the high-risk E6 and E7 proteins in the development of cancer, few have looked at their role in the progression from productive infection to LSIL and HSIL+, which can occur soon after infection in the absence of integration. I analyze isogenic NIKS lines containing HPV16 episomes, which have previously been shown to have LSIL- or HSIL-like phenotypes in raft culture. In monolayer culture, the HSIL-like cells proliferate more than the LSIL-like cells, and I have found that this appears to be due to the activity of the E6 protein. In contrast, the E7 protein is only able to drive proliferation when the cells are cultured without serum. At confluence, the HSIL-like cells divide to form increasingly small cells in a monolayer, whilst the LSIL-like cells tend to stratify, like the parental line. This indicates that the LSIL- and HSIL-like cells respond differently to cell density. Furthermore I see a similar fast-growing phenotype with an E6 mutant that is unable to bind p53, suggesting that the effect on proliferation is independent of p53 degradation. Increasing or decreasing the levels of E6 leads to LSIL-like cells now having a more HSIL-like growth phenotype or vice versa, respectively. Analysis of contact inhibition signaling pathways shows that the levels of active Notch are significantly higher in the LSIL-like cells. Additionally, I have observed what may be a novel truncated form of active Notch. My results suggest that in productive infections any elevation in cell proliferation in the basal cells may be dependent on E6, while E7-stimulated cell cycle entry may be limited to the suprabasal cells. Aberrant expression of E6 level can then further promote proliferation by overcoming cellular contact inhibition pathways and this contributes to the progression from low- to high-grade lesions.

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