Study of the molecular mechanisms by protein SET with impact on tumorigenesis and progression of oral cancer

• Grant number: 13/10898-4
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2013
• End date: February 29, 2016
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Carlos Curti
• Grantee: Carlos Curti
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Carlos Curti

Abstract

This project aims to continue the study of the molecular and biochemical actions of SET protein in tumorigenesis and progression and spread of solid tumors using as model/experimental approach head and neck squamous cell carcinoma (HNSCC). The main front research is based on the impact of this protein in intracellular signaling pathways important for tumorigenesis. At the molecular level, the mechanisms of action of this protein in cancer are not yet completely understood, although several functions have already been described. Recently, our group showed strong accumulation of SET in HNSCC samples, its involvement in the Akt signaling pathway in response to oxidative stress and its potential role in response to DNA damage. Moreover, in the previous project, we obtained evidence that the knockdown for SET in HNSCC cell line changes the level of some miRNAs and RNAs of several transcription factors altered in cancer, a fact that suggests its action in controlling expression. We also obtained evidence of his involvement in cell invasion, epithelial-mesenchymal differentiation, with a strong immune response against tumor xenografts in nude mice from a lineage HNSCC with SET silenced. All these data point to new functions SET protein that may contribute to oral cancer. However, the molecular mechanisms related to the actions described above have not been determined because it depends on further studies. Therefore, in this project we propose to define some of the molecular mechanisms by which the protein SET contributes to tumorigenesis and progression of oral cancer. To answer this question will be used HNSCC cell lineages (HNSCC: HN13, HN12, HN6, CAL-27), NOK-SI (spontaneously immortalized keratinocyte) and lineage kidney HEK293 (all provided by Dr. J.Silvio Gutkind, NIH, USA) after knockdown or overexpression of the protein of interest. Strategies for cellular and molecular biology and biochemistry will be employed in the study of protein functional model using in vitro and in vivo. Western blotting and immunofluorescence methods are used to determine the status (level and phosphorylation) of proteins and distribution in the cell. Various methods and strategies will be used: RNA interference systems, real-time array PCR, real time PCR for miRNA, PCR screening system using a phosphorylated kinase Antibody Array, protein-protein interactions, ELISA, flow cytometry and proliferation cell invasion methylation analysis by PCR and real-time PCR, microscopy, formation of xenograft tumors in nude mice, among others. It is hoped this proposal to identify the molecular mechanisms associated with SET that favor the development and progression of oral cancer, with emphasis on the following specific actions: genomic instability, DNA methylation, miRNA expression, phosphorylation of kinases, epithelial-mesenchymal differentiation, response tumor immune. The approach is multidisciplinary and will expand our understanding on the functions of the SET in oral cancer. (AU)

Scientific publications

(11)

(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)

ALMEIDA, LUCIANA O.; NETO, MARINALDO P. C.; SOUSA, LUCAS O.; TANNOUS, MARYNA A.; CURTI, CARLOS; LEOPOLDINO, ANDREIA M.. SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation. ONCOTARGET, v. 8, n. 16, p. 26802-26818, APR 18 2017. (13/10898-4, 10/20536-4, 13/08135-2, 10/20384-0, 09/52228-0, 09/10783-7)

SOBRAL, LAYS M.; COLETTA, RICARDO D.; ALBERICI, LUCIANE C.; CURTI, CARLOS; LEOPOLDINO, ANDREIA M.. SET/I2PP2A overexpression induces phenotypic, molecular, and metabolic alterations in an oral keratinocyte cell line. FEBS Journal, v. 284, n. 17, p. 2774-2785, SEP 2017. (13/08135-2, 10/18544-9, 13/10898-4)

PADOVANI, KARINA STRINGHETTA; GOTO, RENATA NISHIDA; FUGIO, LAIS BRIGLIADORI; GARCIA, CRISTIANA BERNADELLI; ALVES, VANI MARIA; BRASSESCO, MARIA SOL; GREENE, LEWIS JOEL; REGO, EDUARDO MAGALHAES; LEOPOLDINO, ANDREIA MACHADO. Crosstalk between hnRNP K and SET in ATRA-induced differentiation in acute promyelocytic leukemia. FEBS OPEN BIO, v. 11, n. 7, p. 2019-2032, JUL 2021. (13/01355-7, 13/00374-8, 13/10898-4, 13/08135-2, 16/19103-2)

SOBRAL, LAYS M.; SOUSA, LUCAS O.; COLETTA, RICARDO D.; CABRAL, HAMILTON; GREENE, LEWIS J.; TAJARA, ELOIZA H.; GUTKIND, J. SILVIO; CURTI, CARLOS; LEOPOLDINO, ANDREIA M.. Stable SET knockdown in head and neck squamous cell carcinoma promotes cell invasion and the mesenchymal-like phenotype in vitro, as well as necrosis, cisplatin sensitivity and lymph node metastasis in xenograft tumor models. Molecular Cancer, v. 13, FEB 20 2014. (10/18544-9, 09/52228-0, 13/08135-2, 10/20384-0, 13/10898-4)

ALMEIDA, LUCIANA O.; GARCIA, CRISTIANA B.; MATOS-SILVA, FLAVIA A.; CURTI, CARLOS; LEOPOLDINO, ANDREIA M.. Accumulated SET protein up-regulates and interacts with hnRNPK, increasing its binding to nucleic acids, the Bcl-xS repression, and cellular proliferation. Biochemical and Biophysical Research Communications, v. 445, n. 1, p. 196-202, FEB 28 2014. (07/02223-6, 09/52228-0, 09/10783-7, 10/20384-0, 13/10898-4)

ALMEIDA, LUCIANA O.; GOTO, RENATA N.; NETO, MARINALDO P. C.; SOUSA, LUCAS O.; CURTI, CARLOS; LEOPOLDINO, ANDREIA M.. SET overexpression in HEK293 cells regulates mitochondrial uncoupling proteins levels within a mitochondrial fission/reduced autophagic flux scenario. Biochemical and Biophysical Research Communications, v. 458, n. 2, p. 300-306, MAR 6 2015. (09/52228-0, 13/01355-7, 09/10783-7, 10/20384-0, 13/10898-4)

MARIN-PRIDA, JAVIER; LIBERATO, JOSE LUIZ; LLOPIZ-ARZUAGA, ALEXEY; STRINGHETTA-PADOVANI, KARINA; PAVON-FUENTES, NANCY; MACHADO LEOPOLDINO, ANDREIA; GUIROLA CRUZ, OSMANY; HERNANDEZ GONZALEZ, IGNACIO; LEON PEREZ, MARIELA; CAMINS, ANTONI; et al. Novel Insights into the Molecular Mechanisms Involved in the Neuroprotective Effects of C-Phycocyanin against Brain Ischemia in Rats. CURRENT PHARMACEUTICAL DESIGN, v. 28, n. 14, p. 11-pg., 2022-01-01. (13/10898-4, 13/00374-8)

GOTO, RENATA NISHIDA; SOBRAL, LAYS MARTIN; SOUSA, LUCAS OLIVEIRA; GARCIA, CRISTIANA BERNADELLI; LOPES, NORBERTO PEPORINE; MARIN-PRIDA, JAVIER; OCHOA-RODRIGUEZ, ESTAEL; VERDECIA-REYES, YAMILA; LAZARO PARDO-ANDREU, GILBERTO; CURTI, CARLOS; et al. Anti-cancer activity of a new dihydropyridine derivative, VdiE-2N, in head and neck squamous cell carcinoma. European Journal of Pharmacology, v. 819, p. 198-206, JAN 15 2018. (13/01355-7, 13/10898-4)

SOUSA, LUCAS OLIVEIRA; SOBRAL, LAYS MARTIN; DE ALMEIDA, LUCIANA OLIVEIRA; GARCIA, CRISTIANA BERNADELLI; GREENE, LEWIS JOEL; LEOPOLDINO, ANDREIA MACHADO. SET protein modulates H4 histone methylation status and regulates miR-137 level in oral squamous cell carcinoma. Epigenomics, v. 12, n. 6, p. 475-485, MAR 2020. (10/20384-0, 16/19103-2, 13/10898-4, 13/08135-2)

OUCHIDA, AMANDA TOMIE; UYEMURA, VALERIA TUDELLA; QUEIROZ, ANDRE LIMA; BRAUER, VERONICA SOARES; CAVALCANTI-NETO, MARINALDO PACIFICO; SOUSA, LUCAS OLIVEIRA; UYEMURA, SERGIO AKIRA; CURTI, CARLOS; LEOPOLDINO, ANDREIA MACHADO. SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, v. 1866, n. 4, p. 623-637, APR 2019. (09/52228-0, 13/10898-4, 16/19103-2)

GOTO, RENATA NISHIDA; SOBRAL, LAYS MARTIN; STRINGHETTA-PADOVANI, KARINA; GARCIA, CRISTIANA B.; DA SILVA, GABRIEL; VITEK, MICHAEL P.; LEOPOLDINO, ANDREIA MACHADO. Synergic effect of OP449 and FTY720 on oral squamous cell carcinoma. European Journal of Pharmacology, v. 882, SEP 5 2020. (13/00374-8, 13/01355-7, 13/10898-4, 18/17480-9, 16/19103-2, 13/08135-2)