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SET protein in head and neck squamous cell carcinoma

Grant number: 05/03380-2
Support type:Scholarships abroad - Research
Effective date (Start): April 20, 2006
Effective date (End): September 19, 2006
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Andréia Machado Leopoldino
Grantee:Andréia Machado Leopoldino
Host: J. Silvio Gutkind
Home Institution: Pessoa Física
Local de pesquisa : National Institutes of Health, Bethesda (NIH), United States  

Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancy worldwide, representing a major international health problem. Patients in early stages frequently exhibit few symptoms, resulting in diagnosis delay and decrease in survival. Unfortunately, despite intense research and improvements in early detection and therapeutic strategies, the prediction of tumor behavior in this group of neoplasias is still limited and the 5-year survival rate remains low. The development of primary head and neck cancer predicts a greater risk of second cancers occurring in head and neck, lung and esophagus. The above-mentioned data make head and neck cancer an especially interesting group of cancers to be studied by genomic and proteomic techniques. The identification of gene and protein expression profiles in tumors and in their normal counterparts may lead to discover new markers that can distinguish normal from neoplastic cells, and may provide new approaches to the strategy of early prevention, prognosis, treatment and monitoring disease progression. The projects “Analysis of gene expression in head and neck tumors using cDNA microarrays” and Head and Neck Transcriptome identified candidates to molecular markers using RNA analysis in HNSCC. Now, it is important to validate these markers in protein level and to understand its role in tumorigenisis. One of these markers, SET protein, has been studied by us and interesting results have been obtained. The SET (TAF-Ibeta or I-2PP2A) protein, a potent and highly selective inhibitor of PP2A activity that inhibits PP2A-mediated dephosphorylation of Ser10-phosphorylated H3, is detected at transcriptionally active regions of polytene chromosomes in Drosophila melanogaster. Fukukawa et al. (2005) demonstrated that SET negatively regulates cell growth and the MEK/ERK pathway. In fact, SET is one of the cellular proteins that shows interaction with the cyclin-dependent kinase inhibitory protein p21(Cip1) and may participate of cell-cycle regulation. Also, SET is part of a neuronal apoptotic pathway related to Alzheimer's disease via Jcasp-induced apoptosis and tau phosphorylation. The SET is a subunit of the inhibitor of acetyltransferases complex that inhibits histone acetylation by binding to and masking histone acetyltransferase targets. Over expression of SET inhibits demethylation of ectopically methylated DNA resulting in gene silencing and may provide a new mechanism that can explain how hypermethylation of specific regions might come about by inhibition of demethylation in cancer cells. The present study aims to investigate molecular markers of tumor in head and neck carcinomas that may be relevant for prognosis and therapeutic strategies. Specific aims include: (1) to validate SET protein as a molecular marker in HNSCC; (2) to study the role of SET in the regulation of cell proliferation and tumorigenesis; (3) to identify new insights into SET signaling and metabolic pathway that could be useful as therapeutic targets. To achieve these aims, HNSCC samples collected by the Silvio Gutkind´s team of the National Institutes of Health (Oral and Pharyngeal Cancer Branch, DIR, NIH, EUA) will be analyzed. (AU)

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)
LEOPOLDINO, ANDREIA M.; SQUARIZE, CRISTIANE H.; GARCIA, CRISTIANA B.; ALMEIDA, LUCIANA O.; PESTANA, CEZAR R.; SOBRAL, LAYS M.; UYEMURA, SERGIO A.; TAJARA, ELOIZA H.; GUTKIND, J. SILVIO; CURTI, CARLOS. SET protein accumulates in HNSCC and contributes to cell survival: Antioxidant defense, Akt phosphorylation and AVOs acidification. Oral Oncology, v. 48, n. 11, p. 1106-1113, NOV 2012. Web of Science Citations: 23.
LEOPOLDINO, ANDREIA M.; SQUARIZE, CRISTIANE H.; GARCIA, CRISTIANA B.; ALMEIDA, LUCIANA O.; PESTANA, CEZAR R.; POLIZELLO, ANA C. M.; UYEMURA, SERGIO A.; TAJARA, ELOIZA H.; GUTKIND, J. SILVIO; CURTI, CARLOS. Accumulation of the SET protein in HEK293T cells and mild oxidative stress: cell survival or death signaling. Molecular and Cellular Biochemistry, v. 363, n. 1-2, p. 65-74, APR 2012. Web of Science Citations: 19.

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