REGULATION OF CARCINOGENIC HUMAN PAPILLOMAVIRUS GENE EXPRESSION

AIMS: Here we propose to explore the complex mRNA-splicing mechanisms of carcinogenic human papillomaviruses (HPVs) as targets for therapy to HPV-infections and cancer.

We will also investigate the contribution of HPV mRNA-splicing to HPV-carcinogenesis.PLAN: To uncover details of HPV E6 and E7 oncogene mRNA splicing and E1 and E2 mRNA splicing, we will identify cis-acting HPV RNA elements that control splicing via cellular trans-acting factors. We will explore the possibility of targeting HPV mRNA-splicing as antiviral and anti-cancer strategy.

HPV RNA elements may be targeted by antisense LNA oligos and the cellular factors by substances that inhibit protein-modifications that are required for interactions with HPV mRNAs.

To expediate discovery of therapeutic molecules to HPV, we will develop novel bioassays for HPV mRNA splicing use these for library screening to identify small molecules or antisense LNAs that perturb HPV mRNA splicing.MEDICAL SIGNIFICANCE: Carcinogenic HPVs cause more than 600.000 cases of cancer world-wide annually, a number that is expected to increase to over 800.000 cases in year 2040 (WHO).

On the African continent, the number of cancer cases will double.

Premalignant HPV-lesions are currently treated by surgery/ablation and cancer caused by HPV by cold knife and/or radiochemotherapy. Non-invasive therapeutic drugs to HPV are absent but wanted. Obvious targets for therapy to HPV are missing since HPVs do not encode enzymes. Novel targets are needed.