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Regulation of STAT3 activity and the role of secreted STI1/Hop protein in glioblastoma multiforme

Grant number: 12/19019-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2012
Effective date (End): August 31, 2014
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Vilma Regina Martins
Grantee:Bruna Roz Rodrigues
Host Institution: A C Camargo Cancer Center. 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


Glioblastoma Multiforme (GBM) is the type of glial tumor most common and aggressive. Identifying molecules associated with tumor progression might lead to development of new drugs for the treatment of GBM. During the Masters, using tissue microarrays showed that human GBMs exhibit higher expression of STI1/Hop, and that this location has predominantly nuclear when compared to non-neoplastic tissue. Confirming previous data that demonstrated that the group STI1/Hop undergoes a post-translational modification by SUMOylation, we found that the expression of nuclear proteins involved STI1/Hop and the route of SUMOylation, Ubc9 and SUMO 2/3, in human glioblastomas correlates positively. These results were confirmed in GBM cell lines which shows that ectopic expression of E3 ligase enzyme SUMO, PIAS1 leads to an increase in the nuclear localization of STI1/Hop. When expressed ectopically STI1/Hop or enzymes involved in SUMOylation in line glioblastoma observed a nuclear accumulation of STAT3 indicating that both STI1/Hop as SUMOylation may be important for the activity of this transcription factor. Confirming these findings, glioblastomas tissue microarray (TMA) show an increased nuclear localization of STAT3 when these were compared to non-tumor tissue Interestingly, increased nuclear localization of STAT3 in GBMs is not correlated with the increase of their phosphorylated forms. Indicating that other post-translational modifications on this protein may be present in these tumors. According to this hypothesis we show that there is a positive correlation between the nuclear localization of STAT3, Ubc9 and SUMO 2/3. Suggesting that STAT3 could be modified by SUMOylation. Indeed, preliminary results suggest that STAT3 may be SUMOilada. We also update the clinical data of cases of gliomas grouped in TMAs described above. The expression of STI1/Hop and its ligand cellular prion protein (PrPC) has been related to these clinical data show that allowing high expression of PrPC and its ligand STI1/Hop is associated with increased proliferation (positive for the marker Ki-67) and with a lower overall survival These findings led us to start testing in vitro in an attempt to assess whether STAT3 can be activated by the secreted form of STI1/Hop, we know that PrPC binds to the cell surface and activates multiple pathways signaling. Initial data shows that STI1/Hop is capable of activating phosphorylation of STAT3 in a more robust treatment with EGF. Thus, our data indicate that both intracellularly as a secreted STI1/Hop can modulate the activity of STAT3. If confirmed, these data may help to better understand the role of STAT3 in STI1/Hop and glioblastoma multiforme and help identify new therapeutic approaches in these tumors.This project will continue that started in the master determining the mechanisms involved in nuclear translocation of STAT3 and STI1/Hop role in this mechanism. Furthermore, it is also evaluated the role of STI1/Hop secreted in glioblastoma multiforme, and how it contributes to the aggressive phenotype of this type of tumor. (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)
DIAS, MARCOS V. S.; TEIXEIRA, BIANCA L.; RODRIGUES, BRUNA R.; SINIGAGLIA-COIMBRA, RITA; PORTO-CARREIRO, ISABEL; ROFFE, MARTIN; HAJJ, GLAUCIA N. M.; MARTINS, VILMA R.. PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy. AUTOPHAGY, v. 12, n. 11, p. 2113-2128, . (12/19019-0, 10/19200-1, 09/14027-2)
LOPES, M. H.; SANTOS, T. G.; RODRIGUES, B. R.; QUEIROZ-HAZARBASSANOV, N.; CUNHA, I. W.; WASILEWSKA-SAMPAIO, A. P.; COSTA-SILVA, B.; MARCHI, F. A.; BLEGGI-TORRES, L. F.; SANEMATSU, P. I.; et al. Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene, v. 34, n. 25, p. 3305-3314, . (07/08410-2, 12/19019-0, 09/14027-2, 04/12133-6, 10/20796-6)

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