Kazuhiro Tanaka

Kobe University, Kōbe, Hyōgo, Japan

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Publications (38)240.95 Total impact

  • Neurologia i neurochirurgia polska 09/2015; DOI:10.1016/j.pjnns.2015.08.004 · 0.64 Impact Factor
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    ABSTRACT: Increased tumor-associated macrophages (TAMs) have been reported to be associated with poor prognosis in various tumors; however, the importance of TAMs in primary central nervous system lymphoma (PCNSL) has not been clarified. In 47 patients with PCNSL who were treated with high-dose methotrexate (MTX) and radiotherapy, the relationships between the infiltration levels of TAMs and clinicopathological parameters were analyzed. Univariate analysis of the Cox proportional hazards model using continuous scales revealed that increased CD68 positive (+) TAMs was significantly associated with inferior progression free survival (PFS) (p=0.04), and trends were observed for the increased CD163+ TAMs and having shorter PFS (p=0.05). However, increased TAMs were not associated with overall survival. Because TAMs are known to produce various cytokines, we examined the relationships between cerebrospinal fluid (CSF) cytokines and TAMs. CSF interleukin-6 (IL-6) and soluble IL-2 receptor were not correlated with the infiltration rate of TAMs; however, CSF IL-10 level was correlated with infiltration levels of CD68 and CD163+ TAMs. We also confirmed the expression of IL-10 in CD68+ and CD163+ TAMs by double immunostaining analysis. Our results indicate that a high level of IL-10 in CSF may be positively associated with the infiltration level of TAMs in PCNSLs. This article is protected by copyright. All rights reserved.
    Brain Pathology 08/2015; DOI:10.1111/bpa.12318 · 3.84 Impact Factor
  • Kazuhiro Tanaka · Takashi Sasayama · Eiji Kohmura
    Oncotarget 08/2015; 6(29). DOI:10.18632/oncotarget.5263 · 6.36 Impact Factor
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    ABSTRACT: The management of low-grade glioma (LGG) still remains controversial because the effectiveness of early and extensive resection is unclear, and the use of radiation therapy or chemotherapy is not well-defined. In particular, the importance of prognostic factors for survival remains a matter of discussion. The purpose of this study was to validate prognostic factors for survival in patients with LGG. A consecutive series of 55 patients with WHO grade II LGG treated in our institute between 1983 and 2013 were retrospectively reviewed to determine the prognostic factors for survival. All data were retrospectively analyzed from the aspect of baseline characteristics, pathological findings, genetic change, surgical treatments, adjuvant therapies, and survival time. Cox multivariate analysis was performed to determine the prognostic factors for survival. There were 28 patients with diffuse astrocytoma (DA), 21 patients with oligodendroglioma (OG), and 6 patients with oligoastrocytoma (OA) diagnosed on initial surgery. The median overall survival was 193 months and fifteen patients (27.3%) died. A mutation in isocitrate dehydrogenase-1 (IDH1) was found in 72.9% of LGG, and this mutation was positively correlated with methylation of O6-methylguanine-DNA methyltransferase (MGMT) (p=0.02). A better prognosis was significantly associated with combined IDH1 mutation and MGMT methylation status (both positive vs both negative, HR 0.079 [95% CI 0.008-0.579], p=0.012), as well as histology (OG vs DA and OA, HR 0.158 [95% CI 0.022-0.674], p=0.011) and tumor size (<6cm vs ≥6cm, HR 0.120 [95% CI 0.017-0.595], p=0.008). Tumor histology, size and IDH-mutation status are important predictors for prolonged overall survival in patients with LGG and may provide a reliable tool for standardizing future treatment strategies. Copyright © 2015 Elsevier B.V. All rights reserved.
    Clinical neurology and neurosurgery 07/2015; 138:37-44. DOI:10.1016/j.clineuro.2015.07.019 · 1.13 Impact Factor
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    ABSTRACT: Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.
    Proceedings of the National Academy of Sciences 07/2015; 112(30):201511759. DOI:10.1073/pnas.1511759112 · 9.67 Impact Factor
  • Brain Pathology 07/2015; 25(4):509-510. DOI:10.1111/bpa.12270 · 3.84 Impact Factor
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    ABSTRACT: Primary central nervous system lymphoma (PCNSL) manifest aggressive clinical behavior and have poor prognosis. Although constitutive activation of the nuclear factor-κB (NF-κB) pathway has been documented, knowledge about the genetic alterations leading to the impairment of the NF-κB pathway in PCNSLs is still limited. This study was aimed to unravel the underlying genetic profiles of PCNSL. We conducted the systematic sequencing of 21 genes relevant to the NF-κB signaling network for 71 PCNSLs as well as the pyrosequencing of CD79B and MYD88 mutation hotspots in a further 35 PCNSLs and 46 glioblastomas (GBMs) for validation. The results showed that 68 out of 71 PCNSLs had mutations in the NF-κB gene network, most commonly affecting CD79B (83%), MYD88 (76%), TBL1XR1 (23%), PRDM1 (20%) and CREBBP1 (20%). These mutations, particularly CD79B and MYD88, frequently coincided within each tumor in various combinations, simultaneously affecting diverse pathways within the network. No GBMs had hotspot mutation of CD79B Y196 and MYD88 L265. The prevalence of CD79B and MYD88 mutations in PCNSLs was considerably higher than reported in systemic diffuse large B-cell lymphomas. This observation could reflect the paucity of antigen stimuli from the immune system in the central nervous system (CNS) and the necessity to substitute them by the constitutive activation of CD79B and MYD88 that would initiate the signaling cascades. These hotspot mutations may serve as a genetic hallmark for PCNSL serving as a genetic marker for diagnose and potential targets for molecular therapy. This article is protected by copyright. All rights reserved.
    Neuropathology and Applied Neurobiology 06/2015; DOI:10.1111/nan.12259 · 3.93 Impact Factor
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    ABSTRACT: Signal transducers and activators of transcription 3 (STAT3) are activated by various cytokines and oncogenes; however, the activity and pathogenesis of STAT3 in diffuse large B cell lymphoma of the central nervous system have not been thoroughly elucidated. We investigated the phosphorylation levels of STAT3 in 40 specimens of primary central nervous system diffuse large B-cell lymphoma (PCNS DLBCL) and analyzed the association between phsopho-STAT3 (pSTAT3) expression and cerebrospinal fluid (CSF) concentration of interleukin-10 (IL-10) or IL-6. Immunohistochemistry and Western blot analysis revealed that most of the specimens in PCNS DLBCL expressed pSTST3 protein, and a strong phosphorylation levels of STAT3 was statistically associated with high CSF IL-10 levels, but not with CSF IL-6 levels. Next, we demonstrated that recombinant IL-10 and CSF containing IL-10 induced the phosphorylation of STAT3 in PCNS DLBCL cells. Furthermore, molecular subtype classified by Hans' algorithm was correlated with pSTAT3 expression levels and CSF IL-10 levels. These results suggest that the STAT3 activity is correlated with CSF IL-10 level, which is a useful marker for STAT3 activity in PCNS DLBCLs.
    Journal of Neuro-Oncology 06/2015; DOI:10.1007/s11060-015-1843-9 · 3.07 Impact Factor
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    ABSTRACT: Radiation-induced vasculopathy is a complication of radiation therapy. Most reports regarding post-irradiation ischemic stroke with intracranial tumors are restricted to pediatric cases. Here we report two adult cases of delayed brain infarction due to anterior and middle cerebral artery stenosis or occlusion seemingly caused by focal radiation therapy for malignant glioma. Although radiation-induced ischemic stroke in adults is relatively uncommon, it is possible that the morbidity rate of radiation-induced stroke in malignant glioma patients will increase with prolonged survival due to advances in therapy. Therefore, regular evaluation of intracranial vasculature following radiation therapy is necessary.
    No shinkei geka. Neurological surgery 04/2015; 43(4):344-351. DOI:10.11477/mf.1436203018 · 0.13 Impact Factor
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) is hyperactivated in many types of cancer, rendering it a compelling drug target; however, the impact of mTOR inhibition on metabolic reprogramming in cancer is incompletely understood. Here, by integrating metabolic and functional studies in glioblastoma multiforme (GBM) cell lines, preclinical models, and clinical samples, we demonstrate that the compensatory upregulation of glutamine metabolism promotes resistance to mTOR kinase inhibitors. Metabolomic studies in GBM cells revealed that glutaminase (GLS) and glutamate levels are elevated following mTOR kinase inhibitor treatment. Moreover, these mTOR inhibitor-dependent metabolic alterations were confirmed in a GBM xenograft model. Expression of GLS following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate-dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and GLS resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance.
    The Journal of clinical investigation 03/2015; 125(4). DOI:10.1172/JCI78239 · 13.22 Impact Factor
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    ABSTRACT: Background: We compared the diagnostic yield and morbidity by frame-based computed tomography-guided stereotactic biopsy (CTSTB) with Brown-Roberts-Wells (BRW) unit and by neuronavigation-guided frameless stereotactic biopsy (NSTB) using magnetic resonance imaging (MRI). Methods: The subjects’ age range was 15-83 years. CTSTB with BRW unit was performed for 59 tumors (58 cases, 1988-2007). NSTB was performed for 38 tumors (35 cases, 2007-2013) with the needle sheath attached to the head holder. By NSTB, target locations of sampling points and trajectories were confirmed by using MRI. Diffusion tensor imaging-based fiber tractography was used to achieve safe trajectories. STB by using BRW did not visualize the trajectory virtually; however, the planning images for NSTB were able to show the trajectory virtually before the procedure. Results: Histological diagnoses were established for 93 tumors at the first biopsy. The diagnostic yield was 94.9% by CTSTB and 97.4% by NSTB (P = 0.944). The morbidity rate was 5.1% by CTSTB and 0% by NSTB (P = 0.417). The absolute risk reduction was 23.1% by NSTB when the targets were basal ganglia (putamen, globus pallidus) or thalamus. In the cases of glioma for which the targets were basal ganglia (putamen, globus pallidus) or thalamus, the absolute risk reduction by NSTB was 30%. Conclusions: There was no significant difference between CTSTB and NSTB concerning the diagnostic yield and morbidity. However, when the target is the basal ganglia (putamen, globus pallidus) or thalamus and glioma is suspected, NSTB by using MRI with virtual trajectory is preferable to CTSTB concerning morbidity.
    Surgical Neurology International 09/2014; 5(Suppl 8):S421-6. DOI:10.4103/2152-7806.140211 · 1.18 Impact Factor
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    ABSTRACT: Here, we describe an extremely rare case of angiosarcoma arising in schwannoma of the cerebellopontine angle and later associating with meningioma in a patient with neurofibromatosis type 2. A 33-year-old disabled Japanese man with right drop foot after surgery for an unspecified tumor demonstrated multiple tumors, suspected to be schwannoma, in the bilateral cerebellopontine angles, the cervical and lumbar spinal cord, and on the right nuchal skin. Also present were several tumors in the medulla and thoracic spinal cord suspected to be ependymoma or astrocytoma. The patient was diagnosed with neurofibromatosis type 2 according to the diagnostic criteria by the U.S. National Institutes of Health. The bilateral tumors in the cerebellopontine angle were resected to reduce symptoms and brain stem compression. Histopathological analysis revealed angiosarcoma arising in schwannoma of the bilateral tumors, and angiosarcoma was proportionally larger in the right tumor than in the left. At age 36, the patient underwent a second resection of the regrown tumor in the left cerebellopontine angle, and histopathology demonstrated mixed angiosarcoma and meningioma. That angiosarcoma arises in schwannoma is a pathogenesis within the realm of conjecture, especially that the phenomenon of mixed meningioma and angiosarcoma has not been reported to date.
    Brain Tumor Pathology 03/2014; 31(4). DOI:10.1007/s10014-014-0180-6 · 1.22 Impact Factor
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    ABSTRACT: Background: MRI group analysis is a powerful tool for elucidating pathological conditions in the brain that are challenging to reveal from single subject analysis. This research aimed to elucidate special distribution characteristics of primary central nervous system lymphoma (PCNSL) within the brain with respect to molecular marker expression patterns. Methods: MR images from 100 treatment-naive PCNSL patients were collected and registered onto averaged standard anatomical MRI (MNI152). Gadolinium-enhanced lesions were extracted, and a lesion frequency map was created. Lymphoma subtypes were classified as germinal center B (GCB) or non-GCB by immunohistochemistry in 90 patients. Results: A PCNSL frequency map showed that these tumors tended to occur around the lateral, third and fourth ventricles. Moreover, GCB (27 cases) and non-GCB (63 cases) PCNSL frequency maps showed GCB lymphomas located at the upper tegmentum and cerebellum around the fourth ventricle, while non-GCB lymphomas tended to occupy the anterior fornix. These differences were significant and confirmed by the existence of voxels with P values <.05 (random permutation analysis with voxel-wise Fisher' exact test). This is the very first report to address phenotypical and spatial distributional differences between GCB and non-GCB PCNSL using an MR group analytical method.
    Neuro-Oncology 02/2014; 16(5). DOI:10.1093/neuonc/not319 · 5.56 Impact Factor
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    ABSTRACT: Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
    Cell metabolism 10/2013; 18(5). DOI:10.1016/j.cmet.2013.09.013 · 17.57 Impact Factor
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    ABSTRACT: mTOR pathway hyperactivation occurs in nearly 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacological strategy to overcome it. We performed in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin resistant signaling and blocking GBM growth and a novel single cell technology, DNA Encoded Antibody Libraries, was used to identify mechanisms of resistance. Here we demonstrate that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling; block mTORC2 signaling and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes GBM cells and orthotopic xenografts to CC214-1 and CC214-2 induced cell death. These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in GBM and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. This study also demonstrates a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacological strategy for overcoming it.
    Clinical Cancer Research 09/2013; 19(20). DOI:10.1158/1078-0432.CCR-13-0527 · 8.72 Impact Factor
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    ABSTRACT: Alternative splicing contributes to diverse aspects of cancer pathogenesis including altered cellular metabolism, but the specificity of the process or its consequences are not well understood. We characterized genome-wide alternative splicing induced by the activating EGFRvIII mutation in glioblastoma (GBM). EGFRvIII upregulates the heterogeneous nuclear ribonucleoprotein (hnRNP) A1 splicing factor, promoting glycolytic gene expression and conferring significantly shorter survival in patients. HnRNPA1 promotes splicing of a transcript encoding the Myc-interacting partner Max, generating Delta Max, an enhancer of Myc-dependent transformation. Delta Max, but not full-length Max, rescues Myc-dependent glycolytic gene expression upon induced EGFRvIII loss, and correlates with hnRNPA1 expression and downstream Myc-dependent gene transcription in patients. Finally, Delta Max is shown to promote glioma cell proliferation in vitro and augment EGFRvIII expressing GBM growth in vivo. These results demonstrate an important role for alternative splicing in GBM and identify Delta Max as a mediator of Myc-dependent tumor cell metabolism.
    Cell metabolism 05/2013; 17(6). DOI:10.1016/j.cmet.2013.04.013 · 17.57 Impact Factor
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    ABSTRACT: Unlabelled: Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here, we show the first example of this alternate mechanism in brain tumors by showing that EGF receptor (EGFR)-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing platelet-derived growth factor receptor β (PDGFRβ). Mechanistic studies show that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1- and extracellular signal-regulated kinase-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, nongenetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy. Significance: These results provide the fi rst clinical and biologic evidence for receptor tyrosinekinase (RTK) "switching" as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become "addicted" to a non amplified, nonmutated, physiologically regulated RTK to evade targeted treatment.
    Cancer Discovery 03/2013; 3(5). DOI:10.1158/2159-8290.CD-12-0502 · 19.45 Impact Factor
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    ABSTRACT: Metabolomics has recently undergone rapid development; however, metabolomic analysis in cerebrospinal fluid (CSF) is not a common practice. We analyzed the metabolite profiles of preoperative CSF samples from 32 patients with histologically confirmed glioma using gas chromatography/mass spectrometry (GC/MS). We assessed how alterations in the metabolite levels were related to the World Health Organization (WHO) tumor grades, tumor location, gadolinium enhancement on magnetic resonance imaging (MRI), and the isocitrate dehydrogenase (IDH) mutation status. Sixty-one metabolites were identified in the CSF from glioma patients using targeted, quantitative and non-targeted, semi-quantitative analysis. The citric and isocitric acid levels were significantly higher in the glioblastoma (GBM) samples than in the grades I–II and grade III glioma samples. In addition, the lactic and 2-aminopimelic acid levels were relatively higher in the GBM samples than in the grades I–II glioma samples. The CSF levels of the citric, isocitric, and lactic acids were significantly higher in grade I–III gliomas with mutant IDH than in those with wild-type IDH. The tumor location and enhancement obtained using MRI did not significantly affect the metabolite profiles. Higher CSF levels of lactic acid were statistically associated with a poorer prognosis in grades III–IV malignant gliomas. Our study suggests that the metabolomic analysis of CSF from glioma patients may be useful for predicting the glioma grade, metabolic state, and prognosis of gliomas. Electronic supplementary material The online version of this article (doi:10.1007/s11060-013-1090-x) contains supplementary material, which is available to authorized users.
    Journal of Neuro-Oncology 03/2013; 113(1). DOI:10.1007/s11060-013-1090-x · 3.07 Impact Factor
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    ABSTRACT: Introduction: Preoperative knowledge of the position of the facial nerve relative to a vestibular schwannoma would be very helpful to decide for an adapted therapeutic strategy. The aim of this study is to assess the feasibility of predicting the course of the facial nerve in vestibular schwannoma patients using 3 T high-resolution magnetic resonance cisternography in a large consecutive series. Methods: The study was prospectively conducted in 82 patients operated for vestibular schwannoma. All patients underwent preoperative gadolinium (Gd)-enhanced, balanced fast-field echo (bFFE) imaging. The course of the facial nerve was estimated preoperatively and the results were verified with the intraoperative findings. Results: The facial nerve could be identified by preoperative MRI in 38 cases (46.3 %). In 28 cases (34.1 % of total patients, 73.7 % of identified patients), the course of the MRI-identified facial nerve was completely congruent with the intraoperative findings. In the patient group with MRI-identified facial nerves, tumor size was smaller and the number of solid type was larger. There were 23 cases where the tumor was solid and smaller than 20 mm. Nineteen (82.6 %) of those cases could estimate the facial nerve preoperatively and 16 cases (69.6 %) have complete congruency. Conclusion: Gd-enhanced bFFE at 3 T is capable of demonstrating the location of the facial nerve in vestibular schwannoma patients prior to surgery. Slices that were perpendicular to the internal auditory canal were useful besides axial images. In small, solid-type tumors, facial nerve was more easily identified than other types of tumors.
    Neuroradiology 02/2013; 55(5). DOI:10.1007/s00234-013-1156-7 · 2.49 Impact Factor
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    ABSTRACT: MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and contribute to cell proliferation, differentiation and metabolism. Our previous study revealed the extensive modulation of a set of miRs in malignant glioma. In that study, miR microarray analysis demonstrated the upregulation of microRNA-183 (miR-183) in glioblastomas. Therefore, we examined the expression levels of miR-183 in various types of gliomas and the association of miR-183 with isocitrate dehydrogenase 2 (IDH2), which has complementary sequences to miR-183 in its 3'-untranslated region (3'UTR). In present study, we used real-time PCR analysis to demonstrate that miR-183 is upregulated in the majority of high-grade gliomas and glioma cell lines compared with peripheral, non-tumorous brain tissue. The mRNA and protein expression levels of IDH2 are downregulated via the overexpression of miR-183 mimic RNA in glioma cells. Additionally, IDH2 mRNA expression is upregulated in glioma cells expressing anti-miR-183. We verified that miR-183 directly affects IDH2 mRNA levels in glioma cells using luciferase assays. In malignant glioma specimens, the expression levels of IDH2 were lower in tumors than in the peripheral, non-tumorous brain tissues. HIF-1α levels were upregulated in glioma cells following transfection with miR-183 mimic RNA or IDH2 siRNA. Moreover, vascular endothelial growth factor and glucose transporter 1, which are downstream molecules of HIF-1α, were upregulated in cells transfected with miR-183 mimic RNA. These results suggest that miR-183 upregulation in malignant gliomas induces HIF-1α expression by targeting IDH2 and may play a role in glioma biology.
    Journal of Neuro-Oncology 12/2012; 111(3). DOI:10.1007/s11060-012-1027-9 · 3.07 Impact Factor

Publication Stats

462 Citations
240.95 Total Impact Points


  • 2008–2015
    • Kobe University
      • Division of Neurosurgery
      Kōbe, Hyōgo, Japan
  • 2013
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
    • University of California, San Diego
      San Diego, California, United States
  • 2010–2012
    • University of California, Los Angeles
      • Department of Pathology and Laboratory Medicine
      Los Ángeles, California, United States