Role of Protease Activated Receptor 2 (PAR2) in Human Papillomavirus mediated carcinogenesis

Abstract

HPV-associated cancer is still a relevant public health burden in low-income countries. HPV infection is necessary but not sufficient to induce tumor development in various anatomical sites, such as the uterine cervix, anus, penis, and oropharynx. HPV genome codifies oncoproteins with various known mechanisms as part of cellular transformation and immune system evasion. It is also known that the tumor microenvironment has an important role in tumor progression. Immune cells infiltrate in precursor and malignant lesions. These cells secrete a series of molecules that may have a role in tumor elimination or promotion. Proteases are secreted by tumor cells, mast cells, macrophages, neutrophils, and other granulocytes. HPV-associated tumors are rich in immune cell infiltrate, in part because HPV oncoproteins activate the NFkB pathway in tumor cells, resulting in the secretion of cytokines such as IL-8, which has a chemotactic role. Using the peptide phage display methodology, we identified the PAR2 (Protease Activated Receptor 2) receptor, through tryptase sequence enrichment. Tryptase is an enzyme produced by mast cells. PAR2 may be activated by different proteases and has been described to have a role in carcinogenesis mechanisms. Therefore, we are working with the hypothesis that the HPV tumor microenvironment contributes to the carcinogenesis process through PAR2 activation. When activated, PAR2 would activate signaling pathways that cooperate with HPV oncoproteins in the cellular transformation process. To test this hypothesis, we will treat immortalized, and HPV-transformed cell lines with PAR2 agonists and antagonists, and we will measure proliferation, viability, migration, and substrate-independent growth. We will also incubate the cells with neutrophils, a very frequent leukocyte population in cervical cancer, which is the best-characterized HPV-induced tumor. We will test if neutrophil elastase can activate PAR2 and contribute to cellular transformation. Our results will contribute to the understanding of HPV-mediated carcinogenesis mechanisms and will give us a basis for the development of new therapeutics against these cancer types.