Research

Role of APOBEC proteins in the oncogenesis of HPV viruses

Code:

J3-2518

Range:

01. September 2020 - 31. August 2023

Range:

0.41 FTE

Leader:

Marija Nika Lovšin

Field:

3.01 Medical sciences/ Microbiology and immunology

Abstract:

Human papillomaviruses (HPV) are one of the most prevalent sensually transmitted pathogens, responsible for more than 5 % of all cancers in humans, including cervical cancer and HPV-associated head-and-neck cancer. APOBEC3 (A3) proteins are cytidine deaminases that are capable of DNA and RNA editing. DNA-editing activity represent a key part of the innate immune response to viral infections. However, this intrinsic host defence mechanism may also be responsible for the long-term host DNA hyper-mutation and cancer development. Recent wide-genome studies have exposed APOBECs as a primary source of somatic mutations in cervical cancer, while the molecular mechanisms of oncogenesis remain largely unknown. The progression from precursor lesions to invasive cervical cancer is influenced by persistent HPV infection, which induces changes in the host genome and epigenome. Our long-term objective is to clarify the role of APOBEC proteins in the oncogenesis of HPV viruses. We will address these processes from various perspectives including biostatistical analysis of big data, genetic studies as well as molecular and cell biology experiments. Our specific aims are (i) to analyse genetic and epigenetic changes triggered by APOBEC3 expression in cervical cancer samples and HPV model systems, and (ii) to elucidate critical timing and mechanisms of APOPBEC-driven cell transformation in HPV infected host cells. The project will be performed in consortium of three project partners with complementary expertise. The study will be divided into four work packages. First part (WP1) will be dedicated to integrative analysis of the cervical cancer clinical datasets collected in the The Cancer Genome Atlas (TCGA), emphasising expression of A3 proteins in cervical cancer samples in correlation to host/viral genome methylation and expression of miRNA. Second part of the project (WP2) will employ HPV model systems, mimicking different stages of HPV infection. We will study, (i) when APOBEC mutations start to accumulate, (ii) whether APOBEC mutations occur before non-APOBEC mutations and (iii) whether non-editing activity of A3 proteins is involved in these processes. The last part of the project (WP3 and 4) will be focused on the mechanisms of APOBEC-driven transformation in HPV infected cells. Results of the study will substantially contribute to the existing knowledge on the involvement of APOBEC proteins in HPV-related oncogenesis and will advance the research progress in other viral infections regulated by APOBEC proteins, like other small DNA tumour viruses, which is a recent highlight in the APOBEC-virus research. Bio statistical analysis of clinical data will be focused primarily on identifying biomarkers with high prognostic potential. Understanding the somatic events following HPV infection and persistence can aid the development of early detection biomarkers, particularly when mutations in precancers are characterized. Somatic mutations can also profoundly influence prognosis and treatment decisions.