SUELI MIEKO OBA SHINJO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
10 resultados
Resultados de Busca
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- Activation of Neural and Pluripotent Stem Cell Signatures Correlates with Increased Malignancy in Human Glioma(2011) HOLMBERG, Johan; HE, Xiaobing; PEREDO, Inti; ORREGO, Abiel; HESSELAGER, Goran; ERICSSON, Christer; HOVATTA, Outi; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; NISTER, Monica; MUHR, JonasThe presence of stem cell characteristics in glioma cells raises the possibility that mechanisms promoting the maintenance and self-renewal of tissue specific stem cells have a similar function in tumor cells. Here we characterized human gliomas of various malignancy grades for the expression of stem cell regulatory proteins. We show that cells in high grade glioma co-express an array of markers defining neural stem cells (NSCs) and that these proteins can fulfill similar functions in tumor cells as in NSCs. However, in contrast to NSCs glioma cells co-express neural proteins together with pluripotent stem cell markers, including the transcription factors Oct4, Sox2, Nanog and Klf4. In line with this finding, in high grade gliomas mesodermal-and endodermal-specific transcription factors were detected together with neural proteins, a combination of lineage markers not normally present in the central nervous system. Persistent presence of pluripotent stem cell traits could only be detected in solid tumors, and observations based on in vitro studies and xenograft transplantations in mice imply that this presence is dependent on the combined activity of intrinsic and extrinsic regulatory cues. Together these results demonstrate a general deregulated expression of neural and pluripotent stem cell traits in malignant human gliomas, and indicate that stem cell regulatory factors may provide significant targets for therapeutic strategies.
- The Genetic Landscape of the Childhood Cancer Medulloblastoma(2011) PARSONS, D. Williams; LI, Meng; ZHANG, Xiaosong; JONES, Sian; LEARY, Rebecca J.; LIN, Jimmy Cheng-Ho; BOCA, Simina M.; CARTER, Hannah; SAMAYOA, Josue; BETTEGOWDA, Chetan; GALLIA, Gary L.; JALLO, George I.; BINDER, Zev A.; NIKOLSKY, Yuri; HARTIGAN, James; SMITH, Doug R.; GERHARD, Daniela S.; FULTS, Daniel W.; VANDENBERG, Scott; BERGER, Mitchel S.; MARIE, Suely Kazue Nagahashi; SHINJO, Sueli Mieko Oba; CLARA, Carlos; PHILLIPS, Peter C.; MINTURN, Jane E.; BIEGEL, Jaclyn A.; JUDKINS, Alexander R.; RESNICK, Adam C.; STORM, Phillip B.; CURRAN, Tom; HE, Yiping; RASHEED, B. Ahmed; FRIEDMAN, Henry S.; KEIR, Stephen T.; MCLENDON, Roger; NORTHCOTT, Paul A.; TAYLOR, Michael D.; BURGER, Peter C.; RIGGINS, Gregory J.; KARCHIN, Rachel; PARMIGIANI, Giovanni; BIGNER, Darell D.; YAN, Hai; PAPADOPOULOS, Nick; VOGELSTEIN, Bert; KINZLER, Kenneth W.; VELCULESCU, Victor E.Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
- Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma(2011) UNO, Miyuki; OBA-SHINJO, Sueli Mieko; CAMARGO, Anamaria Aranha; MOURA, Ricardo Pereira; AGUIAR, Paulo Henrique de; CABRERA, Hector Navarro; BEGNAMI, Marcos; ROSEMBERG, Sergio; TEIXEIRA, Manoel Jacobsen; MARIE, Suely Kazue NagahashiOBJECTIVES: 1) To correlate the methylation status of the O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter to its gene and protein expression levels in glioblastoma and 2) to determine the most reliable method for using MGMT to predict the response to adjuvant therapy in patients with glioblastoma. BACKGROUND: The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response. METHODS: Fifty-one cases of glioblastoma were analyzed for MGMT promoter methylation by methylation-specific PCR and pyrosequencing, gene expression by real time polymerase chain reaction, and protein expression by immunohistochemistry. RESULTS: MGMT promoter methylation was found in 43.1% of glioblastoma by methylation-specific PCR and 38.8% by pyrosequencing. A low level of MGMT gene expression was correlated with positive MGMT promoter methylation (p = 0.001). However, no correlation was found between promoter methylation and MGMT protein expression (p = 0.297). The mean survival time of glioblastoma patients submitted to adjuvant therapy was significantly higher among patients with MGMT promoter methylation (log rank = 0.025 by methylation-specific PCR and 0.004 by pyrosequencing), and methylation was an independent predictive factor that was associated with improved prognosis by multivariate analysis. DISCUSSION AND CONCLUSION: MGMT promoter methylation status was a more reliable predictor of susceptibility to adjuvant therapy and prognosis of glioblastoma than were MGMT protein or gene expression levels. Methylation-specific polymerase chain reaction and pyrosequencing methods were both sensitive methods for determining MGMT promoter methylation status using DNA extracted from frozen tissue.
- Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma(2011) BETTEGOWDA, Chetan; AGRAWAL, Nishant; JIAO, Yuchen; SAUSEN, Mark; WOOD, Laura D.; HRUBAN, Ralph H.; RODRIGUEZ, Fausto J.; CAHILL, Daniel P.; MCLENDON, Roger; RIGGINS, Gregory; VELCULESCU, Victor E.; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; VOGELSTEIN, Bert; BIGNER, Darell; YAN, Hai; PAPADOPOULOS, Nickolas; KINZLER, Kenneth W.Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.
article 89 Citação(ões) na Scopus Metabolism and Brain Cancer(2011) MARIE, Suely Kazue Nagahashi; SHINJO, Sueli Mieko ObaCellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.- IDH1 mutations in a Brazilian series of Glioblastoma(2011) UNO, Miyuki; OBA-SHINJO, Sueli Mieko; SILVA, Roseli da; MIURA, Flavio; CLARA, Carlos Afonso; ALMEIDA, Jose Reynaldo Walther de; MALHEIROS, Suzana M. F.; BIANCO, Andre Macedo; BRANDT, Reynaldo; RIBAS, Guilherme Carvalhal; FERES, Halim; DZIK, Carlos; ROSEMBERG, Sergio; STAVALE, Joao Norberto; TEIXEIRA, Manoel Jacobsen; MARIE, Suely K. N.
- Mitochondrial DNA depletion and its correlation with TFAM, TFB1M, TFB2M and POLG in human diffusely infiltrating astrocytomas(2011) CORREIA, R. L.; OBA-SHINJO, S. M.; UNO, M.; HUANG, N.; MARIE, S. K. N.Mitochondrial DNA (mtDNA) alterations and their clinical and pathological implications have been analyzed in several human malignancies. A marked decrease in mtDNA copy number along with the increase in malignancy was observed in diffusely infiltrating astrocytomas (24 WHO grade II, 18 grade III, and 78 grade IV or GBM) compared to non-neoplastic brain tissues, being mostly depleted in GBM. Although high relative gene expression levels of mtDNA replication regulators (mitochondrial polymerase catalytic subunit (POLG), transcription factors A (TFAM), B1 (TFB1M) and B2 (TFB2M)) were detected, it cannot successfully revert the mtDNA depletion observed in our samples. On the other hand, a strong correlation among the expression levels of mitochondrial transcription factors corroborates with the TFAM role in the direct control of TFB1M and TFB2M during initiation of mtDNA replication. POLG expression was related to decreased mtDNA copy number, and its overexpression associated with TFAM expression levels also have an impact on long-term survival among GBM patients, interpreted as a potential predictive factor for better prognosis.
article 9 Citação(ões) na Scopus Extraneural metastases in medulloblastoma(2011) MUOIO, Valeria Marques Figueira; SHINJO, Sueli Oba; MATUSHITA, Hamilton; ROSEMBERG, Sergio; TEIXEIRA, Manoel Jacobsen; MARIE, Suely Kazue NagahashiMedulloblastoma is the most common childhood malignant tumor of central nervous system, but it may also occur in adults. It presents high invasive growth with spreading of tumor cells into the leptomeningeal space along the neuroaxis early in the course of the disease. Extraneural metastases are rare but frequently lethal, occurring only in 1 to 5% of patients, and are related, in the most of cases, to the presence of ventriculoperitoneal shunt. Here we characterize the clinical profile of five cases of medulloblastoma with systemic spreading of tumor cells, also comparing them to cases already described in the literature.- ASPM gene expression in medulloblastoma(2011) VULCANI-FREITAS, Tania M.; SABA-SILVA, Najsla; CAPPELLANO, Andrea; CAVALHEIRO, Sergio; MARIE, Sueli K. N.; OBA-SHINJO, Sueli M.; MALHEIROS, Suzana M. F.; TOLEDO, Silvia Regina Caminada deMedulloblastomas are the most common malignant tumors of the central nervous system in childhood. The incidence is about 19-20% between children younger than 16 years old with peak incidence between 4 and 7 years. Despite its sensibility to no specific therapeutic means like chemotherapy and radiotherapy, the treatment is very aggressive and frequently results in regression, growth deficit, and endocrine dysfunction. From this point of view, new treatment approaches are needed such as molecular targeted therapies. Studies in glioblastoma demonstrated that ASPM gene was overexpressed when compared to normal brain and ASPM inhibition by siRNA-mediated inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM gene as a potential molecular target in glioblastoma. The aim of this work was to evaluate ASPM expression in medulloblastoma fragment samples, and to compare the results with the patient clinical features. Analysis of gene expression was performed by quantitative PCR real time using SYBR Green system in tumor samples from 37 children. The t test was used to analyze the gene expression, and Mann-Whitney test was performed to analyze the relationship between gene expressions and clinical characteristics. Kaplan-Meier test evaluated curve survival. All samples overexpressed ASPM gene more than 40-fold. However, we did not find any association between the overexpressed samples and the clinical parameters. ASPM overexpression may modify the ability of stem cells to differentiate during the development of the central nervous system, contributing to the development of medulloblastoma, a tumor of embryonic origin from cerebellar progenitor cells.
- Altered Telomeres in Tumors with ATRX and DAXX Mutations(2011) HEAPHY, Christopher M.; WILDE, Roeland F. de; JIAO, Yuchen; KLEIN, Alison P.; EDIL, Barish H.; SHI, Chanjuan; BETTEGOWDA, Chetan; RODRIGUEZ, Fausto J.; EBERHART, Charles G.; HEBBAR, Sachidanand; OFFERHAUS, G. Johan; MCLENDON, Roger; RASHEED, B. Ahmed; HE, Yiping; YAN, Hai; BIGNER, Darell D.; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; RIGGINS, Gregory J.; KINZLER, Kenneth W.; VOGELSTEIN, Bert; HRUBAN, Ralph H.; MAITRA, Anirban; PAPADOPOULOS, Nickolas; MEEKER, Alan K.