Human papillomavirus (HPV) is the causative agent of squamous cell carcinoma. The infection itself is not sufficient for the transformation of the infected cells but its persistence causes genetic rearrangements, activation of proto-oncogenes and other events, that can generate genomic instability and produce chronic inflammation that strongly correlates with microenvironment conditions increasing the risk of neoplastic transformation. During HPV-related carcinogenesis, tumor microenvironment (TME) switches from an initial immunosuppressive to a proinflammatory feature during the late stage of the disease. Antimicrobial peptides and proteins (AMPs) are small molecules (12-100 amino acid residues) characterized by antimicrobial activity and other functions as homeostasis control, recruitment of immune cells, inflammatory activation, regulation of cell proliferation/differentiation and inhibition of protease activity, defining them as a link between innate and adaptive immune systems. Extracellular vesicles (EVs) can load and deliver a specific package of mediators (e.g. mRNAs, microRNAs, proteins) as well as AMPs in view of their ability to form aggregate with nucleic acids.
The purpose of the project is to investigate the role of AMPs in the modulation of inflammation in the HPV-induced carcinogenesis. Our objective is to verify specific AMPs expression in HPV-16 positive cell lines and their derived EVs. In addition, we will analyze the expression of toll-like receptors (TLR) -7 and TLR-9 in view of the observation that active forms of AMPs can be recognized by these inflammation-related TLR.
The project combines cellular and molecular biology, biotechnology and immunology knowledge with a view to expand current understanding on pathogenic mechanism of HPV infections and related tumors. The working group of the proposing researcher has already been involved in research projects on HPVs. On the basis of our background and expertise on this relevant issue of human health, the goal of the project is to study the role of AMPs in the microenvironment in the HPV-induced carcinogenesis. The present project mainly focuses on the study of the involvement of inflammatory microenvironment in the HPV-induced carcinogenesis, approaching the analysis of the role of the immune molecules as well as their delivery through the extracellular vesicles and in the carcinogenesis process. A new insight evaluated in this project is the possibility that EVs could act carrying the AMPs for amplifying a specific danger stimulus. Accomplishing this task will have also relevant impact on the ongoing development of experimental strategies based on extracellular vesicles delivery and/or stimulation, since it would represent both an original and an efficient way to evaluate the plasticity of TME that in the HPV-induced carcinogenesis shifts from immunosuppressive to a proinflammatory feature.