Transcriptional and posttranscriptional regulation of matrix metalloproteinases inhibitor RECK and its isoforms by viral oncoproteins.

• Grant number: 23/12134-3
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: January 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Enrique Mario Boccardo Pierulivo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Ana Paula Lepique ; Lara Termini ; Sheila Coelho Soares Lima

Abstract

Some types of human papillomavirus (HPV) and the Epstein-Barr virus (EBV) are considered type 1 carcinogens by the International Agency for Research on Cancer (IARC). Together, these viruses are the etiologic factor in approximately 6% of new cancer cases worldwide. Infection with high-risk oncogenic HPV is the etiological factor of practically 100% of uterine cervix carcinomas and more than 90% of anal carcinomas. Furthermore, these viruses are associated with a significant percentage of vulvar, vaginal, penile, and head and neck carcinomas. On the other hand, EBV is associated, in varying percentages, with at least nine different tumors: Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, T/NK cell lymphoma, nasopharyngeal carcinoma, gastric carcinoma and leiomyosarcoma. HPV and EBV express proteins capable of altering the expression and activity of several cellular factors, and disrupting different signal transduction pathways, ensuring the multiplication and persistence of these agents. This is closely associated with the oncogenic potential of these viruses, since the continuous expression of some viral factors is fundamental in the cell transformation process. Furthermore, the establishment and progression of tumors caused by these agents involve a series of complex events that modulate the interaction of the infected cell with neighboring cells and the extracellular environment. Changes in the expression and function of different extracellular matrix (ECM) components, such as matrix metalloproteinases (MMPs) and some of their inhibitors, are involved in the carcinogenesis processes mediated by HPV and EBV. The RECK protein (reversion-inducing cysteine-rich protein with Kazal motifs) is a glycoprotein anchored to the external face of the plasmatic membrane, fundamental in tissue remodeling, wound healing and angiogenesis regulation through the inhibition of MMP-2, MMP-9 and MMP-14. RECK expression levels are inversely correlated with the progression and prognosis of different types of cancers, being considered an important tumor suppressor. Several studies, using different experimental approaches, have shown that the regulation of this gene involves a combination of transcriptional and post-transcriptional mechanisms. Previously, we showed that RECK is down-regulated in HPV-associated tumors and precursor lesions and that its overexpression inhibits the in vitro and in vivo tumorigenic potential of HPV-transformed cell lines. Furthermore, we showed that expression of HPV16 E6 and E7 downregulates RECK promoter activity. However, the molecular mechanisms involved have not been clarified. In the present study we intend to determine the role of HPV and EBV oncoproteins in the regulation of RECK expression and its isoforms. Furthermore, we aim to perform functional studies to determine the involvement of HPV and EBV proteins, specific transcription factors, promoter methylation and microRNAs in the regulation of RECK expression. Finally, we will evaluate the effect of RECK overexpression on tumor establishment and progression in immunocompetent animals. The results of this study will allow a better understanding of RECK regulation mechanisms in the process of carcinogenesis mediated by HPV and EBV. (AU)