Analysis of PAR-2 activity in tumor cell progression via administration of its agonist

• Grant number: 19/18910-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2020
• End date: December 31, 2020
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Ana Paula Lepique
• Grantee: Victor Hideki Yamada
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In the tumor microenvironment, extracellular medium in which tumor cells are located, there are several factors that promote the progression of the disease. Such factors may either directly favor tumor proliferation or indirectly, by altering the local immune response. Human papillomavirus (HPV), for example, can lead to the development of cervical cancer by infecting female genital tract keratinocytes, altering the normal microenvironment to a more favorable for the tumor development. In order to identify molecular targets in uterine cervix tumors, our laboratory performed biopannings using a peptide phage display library against tumor cells derived from uterine cervix tumors, SiHa and HeLa. Among the peptide sequences with high affinity to these cells, we find one with tryptase similarity. Tryptase is an enzyme secreted by mast cells, which has proteolytic activity and is capable of activating the protease activated receptor 2 (PAR-2). As stated in the literature, PAR-2 activation is a mitogenic factor in tumor cells. A project conducted by a doctoral student in the laboratory indicated that mast cells could have an effect on the proliferation of HPV-associated tumor cells. In the project, effects were only observed under culture conditions where there was a ratio of 1: 1 between tumor cells and mast cells.However, this is not observed in any type of tumor in humans. Despite this, the frequency of mast cells is known to increase with tumor progression, and that in experimental models, mast cell activity is important for carcinogenesis. Thus, we hypothesized that mast cells, or tryptase secreted by mast cells, could play a role in the viability and proliferation of immortalized cells. Therefore, this project aims to determine the role of trypsin and activation of PAR-2 in tumor progression in cells immortalized by HPV.