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Inhibition of BMP signaling pathway induced senescence and calcification in anaplastic meningioma
Yokogami K., Watanabe T., Yamashita S., Mizuguchi A., Takeshima H.
Journal of Neuro-Oncology 167 ( 3 ) 455 - 465 2024年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Neuro-Oncology
Purpose: Meningiomas are the most common type of brain tumors and are generally benign, but malignant atypical meningiomas and anaplastic meningiomas frequently recur with poor prognosis. The metabolism of meningiomas is little known, so few effective treatment options other than surgery and radiation are available, and the targets for treatment of recurrence are not well defined. The Aim of this paper is to find the therapeutic target. Methods: The effects of bone morphogenetic protein (BMP) signal inhibitor (K02288) and upstream regulator Gremlin2 (GREM2) on meningioma’s growth and senescence were examined. In brief, we examined as follows: 1) Proliferation assay by inhibiting BMP signaling. 2) Comprehensive analysis of forced expression GREM2.3) Correlation between GREM2 mRNA expression and proliferation marker in 87 of our clinical samples. 4) Enrichment analysis between GREM2 high/low expressed groups using RNA-seq data (42 cases) from the public database GREIN. 5) Changes in metabolites and senescence markers associated with BMP signal suppression. Results: Inhibitors of BMP receptor (BMPR1A) and forced expression of GREM2 shifted tryptophan metabolism from kynurenine/quinolinic acid production to serotonin production in malignant meningiomas, reduced NAD + /NADH production, decreased gene cluster expression involved in oxidative phosphorylation, and caused decrease in ATP. Finally, malignant meningiomas underwent cellular senescence, decreased proliferation, and eventually formed psammoma bodies. Reanalyzed RNA-seq data of clinical samples obtained from GREIN showed that increased expression of GREM2 decreased the expression of genes involved in oxidative phosphorylation, similar to our experimental results. Conclusions: The GREM2-BMPR1A-tryptophan metabolic pathway in meningiomas is a potential new therapeutic target.
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Methionine regulates self-renewal, pluripotency, and cell death of GIC through cholesterol—rRNA axis
Yokogami K., Kikuchi T., Watanabe T., Nakatake Y., Yamashita S., Mizuguchi A., Takeshima H.
BMC Cancer 22 ( 1 ) 1351 2022年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：BMC Cancer
Background: Glioma-initiating cells (GICs) are the source of glioma cells that can self-renew, have pluripotency, and are treatment-resistant, so are the starting point for relapse and eventual death despite multimodality therapy. L-[methyl-11C] methionine PET has observed high accumulation at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. Methods: We cultured cells in methionine-deprived culture medium for comprehensive analysis. Based on the obtained results, the possible target molecules were chemically inhibited and the respective markers were analyzed. Results: Methionine depletion markedly decreased proliferation and increased cell death of GICs. Decreased S-adenosyl-methionine, which is synthesized intracellularly by catalyzed by methionine adenosyltransferase using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotency of stem cells, (iii) decreased expression of the core-genes and pluripotent markers of stem cells including FOXM1, SOX2, SOX4, PROM1, and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2, and (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, small nucleolar RNA guiding the pseudouridylation of 28S rRNA, which is essential for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine depletion and decreases in stem cell markers and small nucleolar RNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project database and compared between tumor cells with relatively low methionine levels in areas of pseudopalisading arrangement around necrosis and tumor cells in the infiltrating region, showing that cells in the infiltrating region have higher capacity to produce cholesterol. Conclusions: Methionine metabolism is closely related with self-renewal, pluripotency, and cell death in GICs through modification of cholesterol biosynthesis, especially in the SREBF2-FOXM1 and ACA43 axis with modification of rRNA.
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Yamashita S., Takeshima H., Kadota Y., Azuma M., Fukushima T., Ogasawara N., Kawano T., Tamura M., Muta J., Saito K., Takeishi G., Mizuguchi A., Watanabe T., Ohta H., Yokogami K.
Brain Tumor Pathology 39 ( 2 ) 88 - 98 2022年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Brain Tumor Pathology
After the new molecular-based classification was reported to be useful for predicting prognosis, the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign has gained interest as one of the promising methods for detecting lower grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutations and chromosome 1p/19q non-codeletion (IDH mut-Noncodel) with high specificity. Although all institutions could use T2-FLAIR mismatch sign without any obstacles, this sign was not completely helpful because of its low sensitivity. In this study, we attempted to uncover the mechanism of T2-FLAIR mismatch sign for clarifying the cause of this sign’s low sensitivity. Among 99 patients with LGGs, 22 were T2-FLAIR mismatch sign-positive (22%), and this sign as a marker of IDH mut-Noncodel showed a sensitivity of 55.6% and specificity of 96.8%. Via pathological analyses, we could provide evidence that not only microcystic changes but the enlarged intercellular space was associated with T2-FLAIR mismatch sign (p = 0.017). As per the molecular analyses, overexpression of mTOR-related genes (m-TOR, RICTOR) were detected as the molecular events correlated with T2-FLAIR mismatch sign (p = 0.020, 0.030. respectively). Taken together, we suggested that T2-FLAIR mismatch sign could pick up the IDH mut-Noncodel LGGs with enlarged intercellular space or that with overexpression of mTOR-related genes.
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Saito K., Yokogami K., Maekawa K., Sato Y., Yamashita S., Matsumoto F., Mizuguchi A., Takeshima H.
Human Cell 34 ( 2 ) 644 - 653 2021年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Cell
TP53 mutations are important molecular markers in diffuse astrocytic tumors and medulloblastomas. We examined the efficacy of a pre-screening method for high-resolution melting (HRM) analysis of TP53 mutation before direct sequencing using samples from patients with diffuse glioma. Surgical samples from 64 diffuse gliomas were classified based on the 2016 World Health Organization (WHO) histopathological grading system and the cIMPACT-NOW (consortium to inform molecular and practical approaches to CNS tumor taxonomy-not official WHO) update. TP53 mutations from exon 5 to exon 8 were assessed by direct sequencing. The results of HRM and p53 immunohistochemistry (IHC) analysis were compared by recording the sensitivity, specificity, and false negative and false positive rates. Direct sequencing detected TP53 mutations in 18 of 64 samples (28.1%): diffuse astrocytoma, IDH-mutant (n = 3); diffuse astrocytoma, IDH-wild type (n = 1); anaplastic astrocytoma, IDH-mutant (n = 3); anaplastic astrocytoma, IDH-wild type (n = 4); and glioblastoma, IDH-wild type (n = 7). A total of 22 mutations was detected in the 18 samples; 4 samples exhibited duplicate missense mutations. Sensitivity and specificity were 0.96 and 0.96, respectively, for HRM analysis; they were 0.89 and 0.52, respectively, for p53 IHC. Overall accuracy was 0.98 for HRM and 0.63 for IHC. HRM analysis is a good pre-screening method for the detection of TP53 mutation before direct sequencing.
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Ecotropic viral integration site 1 regulates EGFR transcription in glioblastoma cells 査読あり
Asako Mizuguchi , Shinji Yamashita, Kiyotaka Yokogami, Kazuhiro Morishita, Hideo Takeshima
journal of neuro-oncology 2019年10月
記述言語：英語 掲載種別：学位論文（博士）
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EVI1によるPDGFRβ転写制御とグリオブラストーマ血管新生機構について
研究課題/領域番号：22K09237 2022年04月 - 2027年03月
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
担当区分：研究代表者
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代謝経路再編成が概日リズム経路を介し、幹細胞性維持、細胞死回避に及ぼす影響の解明
研究課題/領域番号：22K09262 2022年04月 - 2025年03月
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
担当区分：研究分担者