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Regulation of the expression and activity of the matrix metalloproteinase inhibitor RECK by human papillomavirus early proteins: impact on the process of tumor development

Grant number: 19/26065-8
Support type:Regular Research Grants
Duration: November 01, 2020 - April 30, 2023
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal researcher:Enrique Mario Boccardo Pierulivo
Grantee:Enrique Mario Boccardo Pierulivo
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Ana Paula Lepique ; Sheila Coelho Soares Lima

Abstract

Infection with high oncogenic risk human papillomavirus (HPV) types is etiologically associated with almost all cases of cervical cancer, more than 50% of other anogenital carcinomas and a significant percentage of oropharynx tumors. High-risk HPV express two oncoproteins, E6 and E7 that act on specific cellular factors promoting continuous cell proliferation, resistance to apoptosis, resistance to cytokines, immune evasion and numerical and structural chromosomal alterations. Besides, the tumorigenic process associated to HPV infection is characterized by alterations in the components of the extracellular matrix (ECM). The RECK (reversion inducing cysteine rich protein with kazal motifs) protein exhibits an essential function in tissue remodeling and tumor angiogenesis through the post-transcriptional regulation or the metalloproteinases MMP-2, MMP-9 and MMP-14 (MT1-MMP) activity. Studies conducted by our group showed that RECK levels are lower in high-grade cervical lesions and cervical cancer when compared to patients with cervicitis. Moreover, we showed HPV oncogenes expression is associated with RECK down-regulation in cell culture. Furthermore, we demonstrated that RECK super expression reduces the oncogenic potential of cervical cancer derived cell lines in nude mice and that this effect is associated with a clear alteration in the tumor inflammatory infiltrate. Recently, we observed using gene reporter assays that the expression of E6E7 genes is associated with the downregulation of the RECK's gene promoter activity. Altogether, our observations suggest that RECK downregulation may constitute an important step in the natural history of HPV-related tumors. The present study aims to determine the role of RECK in HPV-mediated carcinogenesis in immunocompetent animals. For this purpose we will address the effect of RECK super expression on the tumorigenic potential of TC-1 cells, a model broadly applied to the study of HPV-mediated carcinogenesis. Finally, we aim to study in depth the role of HPV in the regulation of the transcriptional activity of the RECK gene promoter by analyzing the methylation patter of this sequence. The results of this study will contribute to determine the role of RECK in the onset and progression of HPV-associated tumors. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AGUAYO, FRANCISCO; BOCCARDO, ENRIQUE; CORVALAN, ALEJANDRO; CALAF, GLORIA M.; BLANCO, RANCES. nterplay between Epstein-Barr virus infection and environmental xenobiotic exposure in cance. INFECTIOUS AGENTS AND CANCER, v. 16, n. 1, . (19/26065-8)

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