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Regulation of activity of STAT3 for STI1/Hop in glioblastoma.

Grant number: 10/13654-0
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2011
Effective date (End): October 31, 2012
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Vilma Regina Martins
Grantee:Bruna Roz Rodrigues
Home Institution: Hospital A C Camargo. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil
Associated research grant:09/14027-2 - Mechanisms associated with the function of prion protein and its ligand STI1/Hop: therapeutic approaches, AP.TEM

Abstract

Gliomas are tumors derived from glial cells and from their precursors in the CNS. The most common type is the Glioblastoma Multiform (GBM) that presents a devastating malign progression. The proliferation mechanisms and the invasion of this tumor are complex and may involve the signal transduction pathways deregulation. Several molecular targets involved in this pathway were investigated as anticancer therapy, but the results are still unpromising and the survival mean time of the patients with GBM varies from 9 to 12 months. Thus, it is necessary to investigate new molecular pathways that are modified in malignant gliomas which can be useful as a therapeutic target.The STI1/Hop protein, human homologue of co-chaperonin Stress Inducible 1 (STI1), is secreted in high concentrations in GBM cells and promotes cell proliferation in an autocrine "looping" by the binding to the prion protein in the cell membrane. Besides being secreted, STI1/Hop seems to be imported and exported from the cytoplasm to the nucleus. Our preliminary data indicate that a post-translational modification by SUMOylation is involved with STI1/Hop traffic. Furthermore, the group results show that human GBM expresses high levels of STI1/Hop and exhibit nuclear accumulation of this protein when compared to brain tissue. Therefore, our hypothesis is that the traffic and function mechanisms of the STI1/Hop are altered in GBM, contributing to the proliferation and invasion of these tumors.When the expression of the STI1/Hop protein is reduced, the expression and phosphorylation of soluble forms of STAT3 (Signal transducer and activator of transcription-3) decrease, leading to an extranuclear accumulation, what suggests that STI1/Hop can participate in the STAT3 nuclear activation and transduction. STAT3 is known to be a master regulator of mesenchymal transformation, which is a typical phenotype of tumor aggressiveness in human malignant glioma. Besides, studies described a STAT3 aberrant activity in GBM and its role in cell proliferation, apoptosis, angiogenesis and evasion of the immune system. Thus, the goal of this project is to determine how SUMOylation modifications in STI1/Hop and its nuclear translocation may alter the nuclear localization and STAT3 activity in GBM cells.

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)
RODRIGUES, BRUNA R.; QUEIROZ-HAZARBASSANOV, NICOLLE; LOPES, MARILENE H.; BLEGGI-TORRES, LUIS F.; SUZUKI, SERGIO; CUNHA, ISABELA W.; SANEMATSU, PAULO; MARTINS, VILMA R. Nuclear unphosphorylated STAT3 correlates with a worse prognosis in human glioblastoma. PATHOLOGY RESEARCH AND PRACTICE, v. 212, n. 6, p. 517-523, 2016. Web of Science Citations: 5.

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