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
7 resultados
Resultados de Busca
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- Changes in the expression of proteins associated with aerobic glycolysis and cell migration are involved in tumorigenic ability of two glioma cell lines(2012) RAMAO, Anelisa; GIMENEZ, Marcela; LAURE, Helen Julie; IZUMI, Clarice; VIDA, Rodrigo Cesar dos Santos; OBA-SHINJO, Sueli; MARIE, Suely Kazue Nagahashi; ROSA, Jose CesarBackground: The most frequent and malignant brain cancer is glioblastoma multiforme (GBM). In gliomas, tumor progression and poor prognosis are associated with the tumorigenic ability of the cells. U87MG cells (wild-type p53) are known to be tumorigenic in nude mice, but T98G cells (mutant p53) are not tumorigenic. We investigated the proteomic profiling of these two cell lines in order to gain new insights into the mechanisms that may be involved in tumorigenesis. Results: We found 24 differentially expressed proteins between T98G and U87MG cells. Gene Ontology supports the notion that over-representation of differentially expressed proteins is involved in glycolysis, cell migration and stress oxidative response. Among those associated with the glycolysis pathway, TPIS and LDHB are up-regulated in U87MG cells. Measurement of glucose consumption and lactate production suggests that glycolysis is more effective in U87MG cells. On the other hand, G6PD expression was 3-fold higher in T98G cells and this may indicate a shift to the pentose-phosphate pathway. Moreover, GRP78 expression was also three-fold higher in T98G than in U87MG cells. Under thapsigargin treatment both cell lines showed increased GRP78 expression and the effect of this agent was inversely correlated to cell migration. Quantitative RT-PCR and immunohistochemistry of GRP78 in patient samples indicated a higher level of expression of GRP78 in grade IV tumors compared to grade I and non-neoplastic tissues, respectively. Conclusions: Taken together, these results suggest an important role of proteins involved in key functions such as glycolysis and cell migration that may explain the difference in tumorigenic ability between these two glioma cell lines and that may be extrapolated to the differential aggressiveness of glioma tumors.
- Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240(2012) FENTON, Tim R.; NATHANSON, David; ALBUQUERQUE, Claudio Ponte de; KUGA, Daisuke; IWANAMI, Akio; DANG, Julie; YANG, Huijun; TANAKA, Kazuhiro; OBA-SHINJO, Sueli Mieko; UNO, Miyuki; INDA, Maria del Mar; WYKOSKY, Jill; BACHOO, Robert M.; JAMES, C. David; DEPINHO, Ronald A.; VANDENBERG, Scott R.; ZHOU, Huilin; MARIE, Suely K. N.; MISCHEL, Paul S.; CAVENEE, Webster K.; FURNARI, Frank B.Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.
conferenceObject Engagement of cellular prion and heat shock organizing protein as a novel therapeutic target for glioblastoma.(2012) LOPES, M. H.; QUEIROZ-HAZARBASSANOV, N. T.; RODRIGUES, B. R.; SANTOS, T. G.; CUNHA, I. W.; OBA-SHINJO, M.; MARIE, S. K.; MARTINS, V. R.- Overexpression of Ankyrin Repeat Domain Containing Protein 1 Gene (ANKRD1) in Dermatomyositis Muscle Biopsies Is Correlated to Hypoxia and Perifascicular Atrophy(2012) SHINJO, Samuel K.; OBA-SHINJO, Sueli M.; UNO, Miyuki; MARIE, Suely K. N.Background/Purpose: ANKRD1 codes for ankyrin repeat domain containing protein 1, which belongs to the muscle ankyrin repeat protein family involved in a mechano-signaling pathway that links myofibrillar stress response to muscle gene expression. In addition, ANKRD1 has an important role in transcriptional regulation, myofibrillar assembly, cardio-genesis, myogenesis and also possibly in angiogenesis. Microvasculopathy is considered as a cornerstone and early pathological change in dermatomyositis (DM), leading to hypoxia, capillary necrosis and muscle perifascicular atrophy. These alterations could upregulate genes involved in myogenesis and angiogenesis like ANKRD1. Therefore, we analyzed ANKRD1 expression in muscle biopsies of DM patients and correlated with other hypoxia parameters. Methods: RNA was extracted from frozen muscle biopsies samples of 30 untreated adult DM patients (Bohan and Peter’s criteria, 1975). As a control group, we analyzed 20 muscle biopsies with no histological change from untreated adult patients with non-inflammatory myopathy diseases. The gene coding for hypoxia-inducible factor 1, alpha subunit (HIF1A) was analyzed to estimate hypoxia degree. The ANKRD1 and HIF1A transcript expression levels were determined by quantitative real time PCR using Sybr Green method. Perifascicular atrophy was analyzed histologically by semi-quantitative method of HE stained biopsies. Expression and localization of ANKRD1 and HIF1a in muscle biopsies was accessed by immunohistochemistry. Results: Higher ANKRD1 and HIF1A expressions levels were observed in DM relative to control group (p<0.001 and p<0.001). In addition, the expression levels of both genes were correlated (r=0.703, P=0.001). We also observed a positive correlation of both genes to perifascicular atrophy (r=0.420, p=0.023 and r=0.404, p=0.030, respectively). However, ANKRD1 and HIF1A expression levels did not correlate to demographic, clinical and laboratory features (p>0.05). Immunohistochemistry showed that ANKRD1 and HIF1a were expressed mainly by atrophic muscle perifascicular cells. Conclusion: Our results demonstrated ANKRD1 is overexpressed, correlated to HIF1A in perifascicular atrophic fibers of DM muscle specimens. ANKRD1 involvement in myogenesis and angiogenesis mechanism will be further investigated.
- Transcriptional response to GAA deficiency (Pompe disease) in infantile-onset patients(2012) Palermo, A. T.; Palmer, R. E.; So, K. S.; Oba-Shinjo, S. M.; Zhang, M.; Richards, B.; Madhiwalla, S. T.; Finn, P. F.; Hasegawa, A.; Ciociola, K. M.; Pescatori, M.; McVie-Wylie, A. J.; Mattaliano, R. J.; Madden, S. L.; Marie, S. K. N.; Klinger, K. W.; Pomponio, R. J.Pompe disease is a genetic disorder resulting from a deficiency of lysosomal acid alpha-glucosidase (GAA) that manifests as a clinical spectrum with regard to symptom severity and rate of progression. In this study, we used microarrays to examine gene expression from the muscle of two cohorts of infantile-onset Pompe patients to identify transcriptional differences that may contribute to the disease phenotype. We found strong similarities among the gene expression profiles generated from biceps and quadriceps, and identified a number of signaling pathways altered in both cohorts. We also found that infantile-onset Pompe patient muscle had a gene expression pattern characteristic of immature or regenerating muscle, and exhibited many transcriptional markers of inflammation, despite having few overt signs of inflammatory infiltrate. Further, we identified genes exhibiting correlation between expression at baseline and response to therapy. This combined dataset can serve as a foundation for biological discovery and biomarker development to improve the treatment of Pompe disease. (C) 2012 Elsevier Inc. All rights reserved.
article 481 Citação(ões) na Scopus Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas(2012) JIAO, Yuchen; KILLELA, Patrick J.; REITMAN, Zachary J.; RASHEED, B. Ahmed; HEAPHY, Christopher M.; WILDE, Roeland F. de; RODRIGUEZ, Fausto J.; ROSEMBERG, Sergio; OBA-SHINJO, Sueli Mieko; MARIE, Suely Kazue Nagahashi; BETTEGOWDA, Chetan; AGRAWAL, Nishant; LIPP, Eric; PIROZZI, Christopher J.; LOPEZ, Giselle Y.; HE, Yiping; FRIEDMAN, Henry S.; FRIEDMAN, Allan H.; RIGGINS, Gregory J.; HOLDHOFF, Matthias; BURGER, Peter; MCLENDON, Roger E.; BIGNER, Darell D.; VOGELSTEIN, Bert; MEEKER, Alan K.; KINZLER, Kenneth W.; PAPADOPOULOS, Nickolas; DIAZ JR., Luis A.; YAN, HaiMutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas (<10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.- Quantitative proteomic analysis and functional studies reveal that nucleophosmin is involved in cell death in glioblastoma cell line transfected with siRNA(2012) GIMENEZ, Marcela; MARIE, Suely K. N.; OBA-SHINJO, Sueli M.; UNO, Miyuki; SILVA, Roseli da; LAURE, Helen Julie; IZUMI, Clarice; OTAKE, Andreia; CHAMMAS, Roger; ROSA, Jose CesarPreviously, we reported that nucleophosmin (NPM) was increased in glioblastoma multiforme (GBM). NPM is a phosphoprotein related to apoptosis, ribosome biogenesis, mitosis, and DNA repair, but details about its function remain unclear. We treated U87MG and A172 cells with small interference RNA (siRNA) and obtained a reduction of 80% in NPM1 expression. Knockdown at the protein level was evident after the 4th day and was maintained until the 7th day of transfection that was investigated by quantitative proteomic analysis using isobaric tags. The comparison of proteomic analysis of NPM1-siRNA against controls allowed the identification of 14 proteins, two proteins showed increase and 12 presented a reduction of expression levels. Gene ontology assigned most of the hypoexpressed proteins to apoptosis regulation, including GRP78. NPM1 silencing did not impair cell proliferation until the 7th day after transfection, but sensitized U87MG cells to temozolomide (TMZ), culminating with an increase in cell death and provoking at a later period a reduction of colony formation. In a large data set of GBM patients, both GRP78 and NPM1 genes were upregulated and presented a tendency to shorter overall survival time. In conclusion, NPM proved to participate in the apoptotic process, sensitizing TMZ-treated U87MG and A172 cells to cell death, and in association with upregulation of GRP78 may be helpful as a predictive factor of poor prognosis in GBM patients.