The role of nuclear phosphatidylinositol-4,5-bisphosphate in papillomavirus associated cancer development.

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Human papillomaviruses (HPV) constitute of a large family of small DNA viruses, which infect either mucosal or cutaneous epithelia. Oncogenic HPV types can cause cancer at these anatomic sites. Hopes that prophylactic vaccines might substantially reduce the staggering burden of mucosal HPV disease have unfortunately fallen short off their expectations. Therefore, there is an intense interest in unravelling cellular changes unique for oncogenic HPV with the overall goal to identify novel biomarkers in respect to cancer progression as well as the identification of more effective therapeutic targets for the treatment of HPV-associated tumors. The mechanism of cancer progression in patients with persistent papillomavirus infections is not well understood. Recently, we found that nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) levels are high in keratinocytes expressing HPV oncoproteins and in HPV-infected epithelia, resulting in the phospholipidation of nuclear proteins in HPV positive skin cancer as well as HPV16 positive cervical intraepithelial neoplasia and cervical cancer. Elevated PI(4,5)P2 levels seem to be a common phenomenon in oncogenic-HPV infected keratinocytic lesions, since skin tumors which are not triggered by HPV, were found to be PI(4,5)P2 negative. These findings raise important fundamental questions regarding the oncogenic role of PI(4,5)P2 in HPV-induced epidermal cancer development, and whether these findings may also be put to use in future treatment regimens. Thus, the ultimate goal of this proposal is to assess the role of protein-phospholipidation with PI(4,5)P2 in HPV-mediated cancer development, and further determine whether it may serve as a viable novel biomarker for early detection of persistent HPV replication, which very well may turn out to be an effective cancer prevention strategy as well. To this end, we will use cellular models as well as human tumor tissues / tumor biopsies to investigate the specific effects of elevated PI(4,5)P2 levels on keratinocyte physiology. We expect the acquired data to be of pivotal importance in paving the way for the identification of novel molecular pathways and for gaining mechanistic insights into HPV mediated alterations of PI(4,5)P2 pathways and how they may drive epithelial tumor development. Since not only the phospholipid metabolism per se, but also lipid-binding proteins in particular have emerged as promising new targets for pharmacological intervention strategies in various human diseases, targeting these mechanisms in HPV positive keratinocytes may lead to new therapeutic strategies for the treatment of HPV-mediated/induced cancers.