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
13 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 13
- LOX Expression and Functional Analysis in Astrocytomas and Impact of IDH1 Mutation(2015) SILVA, Roseli da; UNO, Miyuki; MARIE, Suely K. Nagahashi; OBA-SHINJO, Sueli M.Lysyl oxidase (LOX) is involved in vital biological processes such as cell motility, cell signaling and gene regulation. Deregulation of this protein can contribute to tumor formation and progression. Although it is known that LOX is involved in invasion, proliferation and tumor migration in other types of tumors, studies of LOX in astrocytomas of different grades are scarce. The purpose of our study was to characterize LOX, BMP1 and HIF1A expression by real-time PCR in astrocytomas with WHO grades I to IV compared to non-neoplastic brain tissue. IDH1 mutational status was determined by PCR and sequencing. LOX protein expression was also analyzed by immunohistochemistry. LOX functional analyses were performed using siRNA knockdown and the specific inhibitor BAPN in two glioblastoma cell lines. The expression levels of LOX, BMP1 and HIF1A were correlated and analyzed according to IDH1 mutation status and to the clinical end-point of overall survival of glioblastoma patients. The results demonstrate that increased expression and activity of LOX, BMP1 and HIF1A were positively correlated with the malignant grade of astrocytomas. LOX protein expression also increased according to the degree of malignancy, with localization in the cytoplasm and nucleus and staining observed in endothelial cells. Glioblastoma with a mutation in IDH1 expressed lower levels of LOX in the nucleus, and IDH1-mutated cases showed lower LOX expression levels when compared to wild-type IDH1 cases. LOX knockdown and inhibition by BAPN in U87MG and A172 cell lines affected migration, invasion and soft agar colony formation. Taken together, these results corroborate the role of LOX in the migration, invasion and angiogenesis of astrocytomas. Furthermore, LOX expression is influenced by IDH1 mutational status. This work provides new insights for researchers aiming to design targeted therapies to control astrocytomas.
- Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival(2015) 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.; SUZUKI, S. H.; OBA-SHINJO, S. M.; MARIE, S. K. N.; TOULMIN, E.; HILL, A. F.; MARTINS, V. R.Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrPC) triggers a large number of trophic effects in the nervous system. We found that both PrPC and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrPC and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrPC binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrPC binding site (HOP230-245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrPC-HOP engagement is a promising approach for GBM therapy.
- Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord(2015) WANG, Yuxuan; SPRINGER, Simeon; ZHANG, Ming; MCMAHON, K. Wyatt; KINDE, Isaac; DOBBYN, Lisa; PTAK, Janine; BREM, Henry; CHAICHANA, Kaisorn; GALLIA, Gary L.; GOKASLAN, Ziya L.; GROVES, Mari L.; JALLO, George I.; LIM, Michael; OLIVI, Alessandro; QUINONES-HINOJOSA, Alfredo; RIGAMONTI, Daniele; RIGGINS, Greg J.; SCIUBBA, Daniel M.; WEINGART, Jon D.; WOLINSKY, Jean-Paul; YE, Xiaobu; OBA-SHINJO, Sueli Mieko; MARIE, Suely K. N.; HOLDHOFF, Matthias; AGRAWAL, Nishant; DIAZ JR., Luis A.; PAPADOPOULOS, Nickolas; KINZLER, Kenneth W.; VOGELSTEIN, Bert; BETTEGOWDA, ChetanCell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.
- CXCR7 and CXCR4 Expressions in Infiltrative Astrocytomas and Their Interactions with HIF1 alpha Expression and IDH1 Mutation(2015) BIANCO, Andre Macedo; UNO, Miyuki; OBA-SHINJO, Sueli Mieko; CLARA, Carlos Afonso; GALATRO, Thais Fernanda de Almeida; ROSEMBERG, Sergio; TEIXEIRA, Manoel Jacobsen; MARIE, Suely Kazue NagahashiThe CXCR7, a new receptor for CXCL12 with higher affinity than CXCR4 has raised key issues on glioma cell migration. The aim of this study is to investigate the CXCR7 mRNA expression in diffuse astrocytomas tissues and to evaluate its interactions with CXCR4 and HIF1 alpha expression and IDH1 mutation. CXCR7, CXCR4 and HIF1 alpha mRNA expression were evaluated in 129 frozen samples of astrocytomas. IDH1 mutation status was analyzed with gene expressions, matched with clinicopathological parameters and overall survival time. Protein expression was analyzed by immunohistochemistry in different grades of astrocytoma and in glioma cell line (U87MG) by confocal microscopy. There was significant difference in the expression levels of the genes studied between astrocytomas and non-neoplasic (NN) controls (p < 0.001). AGII showed no significant correlation between CXCR7/HIF1 alpha (p = 0.548); there was significant correlation between CXCR7/CXCR4 (p = 0.042) and CXCR7/IDH1 (p = 0.008). GBM showed significant correlations between CXCR7/CXCR4 (p = 0.002), CXCR7/IDH1 (p < 0.001) and CXCR7/HIF1 alpha (p = 0.008). HIF1 alpha overexpression was associated with higher expressions of CXCR7 (p = 0.01) and CXCR4 (p < 0.0001), while IDH1 mutation was associated with lower CXCR7 (p = 0.009) and CXCR4 (p = 0.0005) mRNA expressions. Protein expression increased with malignancy and in U87MG cell line was mainly localized in the cellular membrane. CXCR7 was overexpressed in astrocytoma and correlates with CXCR4 and IDH1 in AGII and CXCR4, IDH1 and HIF1 alpha in GBM. Overexpression HIF1 alpha was related with higher expressions of CXCR7 and CXCR4, otherwise IDH1 mutation related with lower expression of both genes. No association between CXCR7 and CXCR4 expression and survival data was related.
- CD99 functional analysis in glioblastoma by RNAseq(2015) OBA-SHINJO, Sueli M.; CARDOSO, Lais C.; SILVA, Roseli da; LERARIO, Antonio M.; UNO, Miyuki; MARIE, Suely S. K.
bookPart Biologia Molecular em Neurologia Clínica(2015) MARIE, Suely Kazue Nagahashi; SHINJO, Sueli Mieko Oba- CoGA: An R Package to Identify Differentially Co-Expressed Gene Sets by Analyzing the Graph Spectra(2015) SANTOS, Suzana de Siqueira; GALATRO, Thais Fernanda de Almeida; WATANABE, Rodrigo Akira; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; FUJITA, AndreGene set analysis aims to identify predefined sets of functionally related genes that are differentially expressed between two conditions. Although gene set analysis has been very successful, by incorporating biological knowledge about the gene sets and enhancing statistical power over gene-by-gene analyses, it does not take into account the correlation (association) structure among the genes. In this work, we present CoGA (Co-expression Graph Analyzer), an R package for the identification of groups of differentially associated genes between two phenotypes. The analysis is based on concepts of Information Theory applied to the spectral distributions of the gene co-expression graphs, such as the spectral entropy to measure the randomness of a graph structure and the Jensen-Shannon divergence to discriminate classes of graphs. The package also includes common measures to compare gene co-expression networks in terms of their structural properties, such as centrality, degree distribution, shortest path length, and clustering coefficient. Besides the structural analyses, CoGA also includes graphical interfaces for visual inspection of the networks, ranking of genes according to their ""importance"" in the network, and the standard differential expression analysis. We show by both simulation experiments and analyses of real data that the statistical tests performed by CoGA indeed control the rate of false positives and is able to identify differentially co-expressed genes that other methods failed.
- Angiotensin-converting enzyme insertion/deletion gene polymorphism is associated with dermatomyositis(2015) SHINJO, Samuel K.; UNO, Miyuki; OBA-SHINJO, Sueli M.; MARIE, Suely K. N.Background and objective: The cornerstone of dermatomyositis (DM) pathogenesis involves vascular disturbance that leads to hypoxia, capillary necrosis and muscle perifascicular atrophy. Hence, the hypothesis is that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism could be associated with susceptibility to DM. Method: A single centre, case control study that genotyped ACE gene in 88 DM and 99 healthy individuals. The ACE gene polymorphism was determined by melting curve analysis of real-time polymerase chain reaction products using SYBR Green. Results: The DM and the control subjects had a comparable mean age, gender frequency and ethnicity. The frequency of the D allele was higher in DM than in the control individuals (63.6% vs 55.6%, respectively). The DM had more ACE D/D and less ACE I/D genotype when compared to the control individuals, whereas the ACE I/I genotype distribution was similar in both case and control groups. Moreover, after sex-age-adjusted analysis, the ACE D/D genotype was strongly associated with DM disease (odds ratio (OR) 2.44, 95% confidence interval (CI): 1.17-4.37), in contrast to ACE I/D genotype (OR 0.51, 95% CI: 0.28-0.93). Conclusions: Homozygous ACE D/D was associated significantly with the DM risk. Further investigations are required to clarify and to confirm the association of these genes with DM susceptibility.
- Immunohistochemical expression of cyclin D1 is higher in supratentorial ependymomas and predicts relapses in gross total resection cases(2015) ANDRADE, Fernanda Goncalves de; MARIE, Suely Kazue Nagahashi; UNO, Miyuki; MATUSHITA, Hamilton; TARICCO, Mario Augusto; TEIXEIRA, Manoel Jacobsen; ROSEMBERG, Sergio; OBA-SHINJO, Sueli MiekoEpendymomas are tumors of the CNS. Although cyclin D1 overexpression has been related to several cancers, its prognostic value in ependymomas has not yet been fully established. We evaluated cyclin D1 expression by an immunohistochemistry analysis of 149 samples of ependymomas, including some relapses, corresponding to 121 patients. Eighty-one patients were adults, 60 were intracranial cases and 92 tumors were grade II. Gross total resection (GTR) was achieved in 62% of cases, and relapse was confirmed in 41.4% of cases. Cyclin D1 protein expression was analyzed by immunohistochemistry and scored with a labeling index (LI) calculated as the percentage of positively stained cells by intensity. We also analyzed expression of CCND1 and NOTCH1 in 33 samples of ependymoma by quantitative real-time PCR. A correlation between cyclin D1 LI score and anaplastic cases (P<0.001), supratentorial location (P<0.001) and age (P=0.001) were observed. A stratified analysis demonstrated that cyclin D1 protein expression was strong in tumors with a supratentorial location, independent of the histological grade or age. Relapse was more frequent in cases with a higher cyclin D1 LI score (P=0.046), and correlation with progression-free survival was observed in cases with GTR (P=0.002). Only spinal canal tumor location and GTR were suggestive markers of PFS in multivarite analyses. Higher expression levels were observed in anaplastic cases for CCND1 (P=0.002), in supratentorial cases for CCND1 (P=0.008) and NOTCH1 (P=0.011). There were correlations between the cyclin D1 mRNA and protein expression levels (P<0.0001) and between CCND1 and NOTCH1 expression levels (P=0.003). Higher cyclin D1 LI was predominant in supratentorial location and predict relapse in GTR cases. Cyclin D1 could be used as an immunohistochemical marker to guide follow-up and treatment in these cases.
- The impact of interleukin-13 receptor expressions in cell migration of astrocytomas(2015) MORETTI, Isabele Fattori; SILVA, Roseli; OBA-SHINJO, Sueli Mieko; CARVALHO, Priscila Oliveira de; CARDOSO, Lais Cavalca; CASTRO, Isac de; MARIE, Suely Kazue NagahashiINTRODUCTION: Astrocytomas are common brain tumors. Increased expression levels of Interleukin-13 Receptor α2 (IL-13RA2) have been reported in astrocytomas. The Interleukin-13 signaling pathway may be associated with cell migration when binding to Interleukin-13 Receptor α1. OBJECTIVE: To investigate Interleukin-13 Receptor α1 (IL-13RA1) and IL13RA2 expression levels in human diffusely infiltrative astrocytomas and test the involvement of Interleukin-13 levels in cell migration in two glioblastoma cell lines. METHODS: IL13RA expression levels were accessed by quantitative real time PCR in 128 samples of astrocytomas and 18 samples of non-neoplastic brain tissues from temporal lobe epilepsy surgery. The impact of IL-13 levels (10 and 20 ng/mL) on cell migration was analyzed by the wound assay in U87MG and A172 cells. RESULTS: Glioblastoma presented higher IL13RA1 and IL13RA2 expression levels compared to lower grades astrocytomas and to non-neoplastic cases. U87MG and A172 cells presented higher expression levels of IL-13RA1 vs. IL-13RA2. A significant difference in migration rate was observed in A172 cells treated with 10 ng/mL of IL-13 vs. control: treated cells presented slower migration than non-treated cells. U87MG cells treated with IL-13 20ng/mL presented slower migration than non-treated cells. This indicates that the IL13Rα1 signaling pathway was not activated, indeed inhibited by the decoy IL-13Rα2, slowing cell migration. This impact occurred with a lesser concentration of IL-13 on the A172 than on the U87MG cell line, because A172 cells have a higher IL-13RA2/A1 ratio. CONCLUSION: The present results suggest IL-13 receptors as possible targets to decrease tumor cell migration.