The effect of RECK or RECK B overexpression in Human Papillomavirus associated cell transformation

• Grant number: 20/15732-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): September 01, 2021
• Effective date (End): August 31, 2024
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Suellen da Silva Gomes Herbster
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Human Papillomavirus (HPV)-induced carcinogenesis comprises alterations in Extracellular Matrix (ECM) components such as Matrix Metalloproteinases (MMP) and their regulators. REversion-inducing Cysteine-rich protein with Kazal motifs (RECK) inhibits the activation of specific MMP and its expression is frequently lost in human cancers. Different mRNA products of RECK gene may be generated by alternative splicing, including RECK B isoform (NM_001316346.2). We have previously reported that RECK overexpression (RECK+) reduced the tumorigenic potential of HPV-transformed cells both in vitro and in vivo. Additionally, we demonstrated that RECK down regulation is a consistent and clinically relevant event in the natural history of Cervical Cancer. Furthermore, RECK+ tumors displayed alterations in intratumoral inflammatory infiltrating cell populations. Here, we aim to evaluate the effect of RECK or RECK B overexpression (RECKB+) in the context of in vivo tumorigenesis, in an immunocompetent murine model and we will explore the content of extracellular vesicles of RECK+ or RECKB+ tumor cells. In a pilot study, we showed that HPV16 E6 and E7 expression was associated with reduced activation of RECK gene promoter. In the second half of the project, as part of an international collaboration with the Infections and Cancer Biology Group led by Dr. Massimo Tommasino, the candidate will carry out chromatin immunoprecipitation assays, complementary gene reporter assays and analysis of RECK and RECK B mRNA expression and stability in HPV16 E6 and/or E7 expressing cells. The data generated in this study will provide further robust evidence on the full potential of RECK as a therapeutic target in Cervical Cancer. (AU)