Updated on 2023/09/12

写真a

 
TSUBOTA Shoma
 
Organization
Graduate School of Medicine Program in Integrated Medicine Biological Chemistry Assistant Professor
Graduate School
Graduate School of Medicine
Undergraduate School
School of Medicine Department of Medicine
Title
Assistant Professor
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Degree 2

  1. Doctor of Philosophy (Medical Science) ( 2017.10   Nagoya University ) 

  2. Master of Medical Science ( 2013.3   Nagoya University ) 

Research Interests 4

  1. Neuroblastoma

  2. Cancer biology

  3. Molecular Biology

  4. 神経芽腫

Research Areas 1

  1. Life Science / Tumor biology

Research History 4

  1. Nagoya University   Department of Molecular Biology, Nagoya University Graduate School of Medicine   Assistant Professor

    2019.4

  2. 名古屋大学大学院医学系研究科分子生物学   助教

    2019.4

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  3. 名古屋大学大学院医学系研究科分子生物学   研究員

    2017.4 - 2019.3

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  4. Japan Society for Promotion of Science

    2014.4 - 2017.3

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Education 1

  1. Nagoya University   Graduate School of Medicine   Program in Integrated Medicine

    2013.4 - 2017.3

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Papers 13

  1. Combination of tumor necrosis factor-α and epidermal growth factor induces the adrenergic-to-mesenchymal transdifferentiation in SH-SY5Y neuroblastoma cells. Reviewed International journal

    Yue Huang, Shoma Tsubota, Nobuhiro Nishio, Yoshiyuki Takahashi, Kenji Kadomatsu

    Cancer science   Vol. 112 ( 2 ) page: 715 - 724   2021.2

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    Neuroblastoma, a type of cancer that is common in children, is composed of two genetically clonal but epigenetically distinct cell types: mesenchymal (MES) and adrenergic (ADRN) types, controlled by super-enhancer-associated lineage-specific transcription factor networks. Mesenchymal-type cells are more migratory, resistant to chemotherapy, and prevalent in relapse tumors. Importantly, both cell types spontaneously transdifferentiate into one another, and this interconversion can be induced by genetic manipulations. However, the mechanisms of their spontaneous transdifferentiation and extracellular factors inducing this phenomenon have not yet been elucidated. Using a unique approach involving gene set enrichment analysis, we selected six ADRN and 10 MES candidate factors, possibly inducing ADRN and MES phenotypes, respectively. Treatment with a combination of 10 MES factors clearly induced the MES gene expression profile in ADRN-type SH-SY5Y neuroblastoma cells. Considering the effects on gene expression profile, migration ability, and chemoresistance, a combination of tumor necrosis factor alpha (TNF-α) and epidermal growth factor (EGF) was sufficient to synergistically induce the ADRN-to-MES transdifferentiation in SH-SY5Y cells. In addition, human neuroblastoma cohort analysis revealed that the expression of TNF and EGF receptors was strongly associated with MES gene expression signatures, supporting their important roles in transdifferentiation in vivo. Collectively, we propose a mechanism of neuroblastoma transdifferentiation induced by extracellular growth factors, which can be controlled in clinical situations, providing a new therapeutic possibility.

    DOI: 10.1111/cas.14760

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  2. Origin and initiation mechanisms of neuroblastoma Reviewed International journal

    Shoma Tsubota, Kenji Kadomatsu

    Cell and Tissue Research   Vol. 372 ( 2 ) page: 211 - 221   2018.5

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Springer Verlag  

    Neuroblastoma is an embryonal malignancy that affects normal development of the adrenal medulla and paravertebral sympathetic ganglia in early childhood. Extensive studies have revealed the molecular characteristics of human neuroblastomas, including abnormalities at genome, epigenome and transcriptome levels. However, neuroblastoma initiation mechanisms and even its origin are long-standing mysteries. In this review article, we summarize the current knowledge about normal development of putative neuroblastoma sources, namely sympathoadrenal lineage of neural crest cells and Schwann cell precursors that were recently identified as the source of adrenal chromaffin cells. A plausible origin of enigmatic stage 4S neuroblastoma is also discussed. With regard to the initiation mechanisms, we review genetic abnormalities in neuroblastomas and their possible association to initiation mechanisms. We also summarize evidences of neuroblastoma initiation observed in genetically engineered animal models, in which epigenetic alterations were involved, including transcriptomic upregulation by N-Myc and downregulation by polycomb repressive complex 2. Finally, several in vitro experimental methods are proposed that hopefully will accelerate our comprehension of neuroblastoma initiation. Thus, this review summarizes the state-of-the-art knowledge about the mechanisms of neuroblastoma initiation, which is critical for developing new strategies to cure children with neuroblastoma.

    DOI: 10.1007/s00441-018-2796-z

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  3. PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma Reviewed International journal

    Shoma Tsubota, Satoshi Kishida, Teppei Shimamura, Miki Ohira, Satoshi Yamashita, Dongliang Cao, Shinichi Kiyonari, Toshikazu Ushijima, Kenji Kadomatsu

    CANCER RESEARCH   Vol. 77 ( 19 ) page: 5259 - 5271   2017.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:AMER ASSOC CANCER RESEARCH  

    Pediatric cancers such as neuroblastoma are thought to involve a dysregulation of embryonic development. However, it has been difficult to identify the critical events that trigger tumorigenesis and differentiate them from normal development. In this study, we report the establishment of a spheroid culture method that enriches early-stage tumor cells from TH-MYCN mice, a preclinical model of neuroblastoma. Using this method, we found that tumorigenic cells were evident as early as day E13.5 during embryo development, when the MYC and PRC2 transcriptomes were significantly altered. Ezh2, an essential component of PRC2, was expressed in embryonic and postnatal tumor lesions and physically associated with N-MYC and we observed that H3K27me3 was increased at PRC2 target genes. PRC2 inhibition suppressed in vitro sphere formation, derepressed its target genes, and suppressed in situ tumor growth. In clinical specimens, expression of MYC and PRC2 target genes correlated strongly and predicted survival outcomes. Together, our findings highlighted PRC2-mediated transcriptional control during embryogenesis as a critical step in the development and clinical outcome of neuroblastoma. (C) 2017 AACR.

    DOI: 10.1158/0008-5472.CAN-16-3144

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  4. Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis. International journal

    Hiroki Kitai, Noritoshi Kato, Koichi Ogami, Shintaro Komatsu, Yu Watanabe, Seiko Yoshino, Eri Koshi, Shoma Tsubota, Yoshio Funahashi, Takahiro Maeda, Kazuhiro Furuhashi, Takuji Ishimoto, Tomoki Kosugi, Shoichi Maruyama, Kenji Kadomatsu, Hiroshi I Suzuki

    BMC biology   Vol. 20 ( 1 ) page: 248 - 248   2022.11

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    BACKGROUND: Combinatorial gene regulation by multiple microRNAs (miRNAs) is widespread and closely spaced target sites often act cooperatively to achieve stronger repression ("neighborhood" miRNA cotargeting). While miRNA cotarget sites are suggested to be more conserved and implicated in developmental control, the pathological significance of miRNA cotargeting remains elusive. RESULTS: Here, we report the pathogenic impacts of combinatorial miRNA regulation on inflammation in systemic lupus erythematosus (SLE). In the SLE mouse model, we identified the downregulation of two miRNAs, miR-128 and miR-148a, by TLR7 stimulation in plasmacytoid dendritic cells. Functional analyses using human cell lines demonstrated that miR-128 and miR-148a additively target KLF4 via extensively overlapping target sites ("seed overlap" miRNA cotargeting) and suppress the inflammatory responses. At the transcriptome level, "seed overlap" miRNA cotargeting increases susceptibility to downregulation by two miRNAs, consistent with additive but not cooperative recruitment of two miRNAs. Systematic characterization further revealed that extensive "seed overlap" is a prevalent feature among broadly conserved miRNAs. Highly conserved target sites of broadly conserved miRNAs are largely divided into two classes-those conserved among eutherian mammals and from human to Coelacanth, and the latter, including KLF4-cotargeting sites, has a stronger association with both "seed overlap" and "neighborhood" miRNA cotargeting. Furthermore, a deeply conserved miRNA target class has a higher probability of haplo-insufficient genes. CONCLUSIONS: Our study collectively suggests the complexity of distinct modes of miRNA cotargeting and the importance of their perturbations in human diseases.

    DOI: 10.1186/s12915-022-01447-4

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  5. Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis

    Akihiro Ryuge, Tomoki Kosugi, Kayaho Maeda, Ryoichi Banno, Yang Gou, Kei Zaitsu, Takanori Ito, Yuka Sato, Akiyoshi Hirayama, Shoma Tsubota, Takashi Honda, Kazuki Nakajima, Tomoya Ozaki, Kunio Kondoh, Kazuo Takahashi, Noritoshi Kato, Takuji Ishimoto, Tomoyoshi Soga, Takahiko Nakagawa, Teruhiko Koike, Hiroshi Arima, Yukio Yuzawa, Yasuhiko Minokoshi, Shoichi Maruyama, Kenji Kadomatsu

    JCI Insight   Vol. 6 ( 20 )   2021.10

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:American Society for Clinical Investigation  

    DOI: 10.1172/jci.insight.142464

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  6. Screening of novel Midkine binding protein by BioID2-based proximity labeling. Reviewed

    Yosuke Komata, Shoma Tsubota, Kazuma Sakamoto, Shinya Ikematsu, Kenji Kadomatsu

    Nagoya journal of medical science   Vol. 83 ( 3 ) page: 495 - 508   2021.8

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    Midkine (MK), a heparin-binding growth factor, is associated with the poor prognosis of the pediatric tumor, neuroblastoma. MK would be a druggable target as many studies showed inhibition of its function in various cancers suppressed tumor developments. To establish the therapy targeting MK, identification of its binding partners, and elucidation of its intracellular signaling are needed. It was reported that exogenous MK induced phosphorylation of ribosomal protein S6 (RPS6) downstream of mTOR signaling. Using RPS6 phosphorylation as a marker of MK response, we searched for MK reactive cell lines. We found that MK cell lines expressing less MK tended to respond better to MK. Next, using an MK reactive neuroblastoma cell line, MK-knocked down SH-SY5Y cells, we employed a proximity-dependent biotin identification method, which was invented to evaluate protein-protein interactions by biotinylation. We confirmed that secreted MK fused to the biotin ligase BioID2 (MK-BioID2) was able to biotinylate proteins from the cells. Biotinylated proteins were identified by liquid chromatography-mass spectrometry analyses. Twenty five proteins were found to be overlapped after three independent experiments, among which insulin-like growth binding protein 2 (IGFBP2) was further analyzed. IGFBP2 was indeed detected with immunoblotting after streptavidin pull down of MK-BioID2 labeled cell extract of MK-knocked down SH-SY5Y cells. Our study suggests that the BioID2 method is useful to identify binding partners of growth factors.

    DOI: 10.18999/nagjms.83.3.495

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  7. Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN-amplified neuroblastoma cells. Reviewed International journal

    Ken Yamashita, Shinichi Kiyonari, Shoma Tsubota, Satoshi Kishida, Ryuichi Sakai, Kenji Kadomatsu

    Cancer science   Vol. 111 ( 7 ) page: 2431 - 2439   2020.7

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    MYCN gene amplification is consistently associated with poor prognosis in patients with neuroblastoma, a pediatric tumor arising from the sympathetic nervous system. Conventional anticancer drugs, such as alkylating agents and platinum compounds, have been used for the treatment of high-risk patients with MYCN-amplified neuroblastoma, whereas molecule-targeting drugs have not yet been approved. Therefore, the development of a safe and effective therapeutic approach is highly desired. Although thymidylate synthase inhibitors are widely used for colorectal and gastric cancers, their usefulness in neuroblastoma has not been well studied. Here, we investigated the efficacies of approved antifolates, methotrexate, pemetrexed, and raltitrexed (RTX), on MYCN-amplified and nonamplified neuroblastoma cell lines. Cell growth-inhibitory assay revealed that RTX showed a superior inhibitory activity against MYCN-amplified cell lines. We found no significant differences in the protein expression levels of the antifolate transporter or thymidylate synthase, a primary target of RTX, among the cell lines. Because thymidine supplementation could rescue the RTX-induced cell growth suppression, the effect of RTX was mainly due to the reduction in dTTP synthesis. Interestingly, RTX treatments induced single-stranded DNA damage response in MYCN-amplified cells to a greater extent than in the nonamplified cells. We propose that the high DNA replication stress and elevated levels of DNA damage, which are a result of deregulated expression of MYCN target genes, could be the cause of increased sensitivity to RTX.

    DOI: 10.1111/cas.14485

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  8. 新規tagmentation-assisted PCR法を用いたCD19キメラ抗原受容体遺伝子導入T細胞の遺伝子挿入部位解析(Integration mapping of CD19 chimeric antigen receptor T cells by novel tagmentation-assisted PCR) Reviewed International journal

    濱田 太立, 奥野 友介, 西尾 信博, 鈴木 哲, 川島 希, 村松 秀城, 坪田 庄真, Wilson Matthew H., 盛田 大介, 片岡 伸介, 市川 大輔, 村上 典寛, 谷口 理恵子, 鈴木 喬悟, 小島 大英, 関屋 由子, 西川 英里, 成田 敦, 濱 麻人, 小島 勢二, 中沢 洋三, 高橋 義行

    臨床血液   Vol. 59 ( 9 ) page: 1586 - 1586   2018.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:(一社)日本血液学会-東京事務局  

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  9. Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR. Reviewed International journal

    Motoharu Hamada, Nobuhiro Nishio, Yusuke Okuno, Satoshi Suzuki, Nozomu Kawashima, Hideki Muramatsu, Shoma Tsubota, Matthew H Wilson, Daisuke Morita, Shinsuke Kataoka, Daisuke Ichikawa, Norihiro Murakami, Rieko Taniguchi, Kyogo Suzuki, Daiei Kojima, Yuko Sekiya, Eri Nishikawa, Atsushi Narita, Asahito Hama, Seiji Kojima, Yozo Nakazawa, Yoshiyuki Takahashi

    EBioMedicine   Vol. 34   page: 18 - 26   2018.8

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    Insertional mutagenesis is an important risk with all genetically modified cell therapies, including chimeric antigen receptor (CAR)-T cell therapy used for hematological malignancies. Here we describe a new tagmentation-assisted PCR (tag-PCR) system that can determine the integration sites of transgenes without using restriction enzyme digestion (which can potentially bias the detection) and allows library preparation in fewer steps than with other methods. Using this system, we compared the integration sites of CD19-specific CAR genes in final T cell products generated by retrovirus-based and lentivirus-based gene transfer and by the piggyBac transposon system. The piggyBac system demonstrated lower preference than the retroviral system for integration near transcriptional start sites and CpG islands and higher preference than the lentiviral system for integration into genomic safe harbors. Integration into or near proto-oncogenes was similar in all three systems. Tag-PCR mapping is a useful technique for assessing the risk of insertional mutagenesis.

    DOI: 10.1016/j.ebiom.2018.07.008

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  10. Development of the sympathoadrenal lineage from neural crest and neuroblastoma Reviewed International journal

    Tsubota Shoma, Kadomatsu Kenji

    CANCER SCIENCE   Vol. 109   page: 22 - 22   2018.1

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  11. Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. Reviewed International journal

    Zhendong Su, Satoshi Kishida, Shoma Tsubota, Kazuma Sakamoto, Dongliang Cao, Shinichi Kiyonari, Miki Ohira, Takehiko Kamijo, Atsushi Narita, Yinyan Xu, Yoshiyuki Takahashi, Kenji Kadomatsu

    Oncotarget   Vol. 8 ( 63 ) page: 106296 - 106310   2017.12

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    Neurocan (NCAN), a secreted chondroitin sulfate proteoglycan, is one of the major inhibitory molecules for axon regeneration in nervous injury. However, its role in cancer is not clear. Here we observed that high NCAN expression was closely associated with the unfavorable outcome of neuroblastoma (NB). NCAN was also highly and ubiquitously expressed in the early lesions and terminal tumor of TH-MYCN mice, a NB model. Interestingly, exogenous NCAN (i.e., overexpression, recombinant protein and conditioned medium) transformed adherent NB cells into spheres whose malignancies in vitro (anchorage-independent growth and chemoresistance) and in vivo (xenograft tumor growth) were potentiated. Both chondroitin sulfate sugar chains and NCAN's core protein were essential for the sphere formation. The CSG3 domain was essential in the moiety of NCAN. Our comprehensive microarray analysis and RT-qPCR of mRNA expression suggested that NCAN treatment promoted cell division, and urged cells to undifferentiated state. The knockdown of NCAN in tumor sphere cells cultured from TH-MYCN mice resulted in growth suppression in vitro and in vivo. Our findings suggest that NCAN, which stimulates NB cells to promote malignant phenotypes, is an extracellular molecule providing a growth advantage to cancer cells.

    DOI: 10.18632/oncotarget.22435

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  12. Neuroblastoma stem cells and CFC1 Reviewed International journal

    Shoma Tsubota, Kenji Kadomatsu

    ONCOTARGET   Vol. 8 ( 28 ) page: 45032 - 45033   2017.7

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    DOI: 10.18632/oncotarget.18464

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  13. Origin and mechanism of neuroblastoma Reviewed International journal

    Shoma Tsubota, Kenji Kadomatsu

    Oncoscience   Vol. 4 ( 7-8 ) page: 70 - 72   2017.7

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Impact Journals LLC  

    Neuroblastoma is the most common extracranial solid tumor in childhood, and develops mainly in the adrenal medulla but also in the sympathetic ganglia. Some cases of neuroblastoma show spontaneous regression. Particularly, stage 4S, where S stands for “special”, exhibits spontaneous regression despite multifocal tumors. Another interesting feature is that, with few exceptions, driver gene mutations are rare in neuroblastoma, while copy number alterations are common, including MYCN amplification, 17q gain, and others, suggesting the involvement of epigenetic regulation [1]. These features suggest that neuroblastoma tumorigenesis is closely related to the development of the sympathoadrenal lineage. However, the underlying mechanisms, even the origin of neuroblastoma, remain largely obscure. To elucidate those mechanisms, three important papers have been recently published [2-4].

    DOI: 10.18632/oncoscience.360

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KAKENHI (Grants-in-Aid for Scientific Research) 4

  1. 神経芽腫の時期・細胞特異的な発生機構解明

    Grant number:22K07186  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    坪田 庄真

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    小児がんの一つである神経芽腫は、様々なゲノム異常とエピゲノム異常が混在し、治療抵抗性から自然退縮まで表現型が極めて多様である。しかし、そもそもなぜ神経芽腫が発生するのか、特にがん化の時期や細胞特異性、神経芽腫を成り立たせる因子(発生に必須の遺伝子)については不明である。本研究では、独自の培養技術とシングルセル遺伝子発現解析の結果を活用し、マウス副腎組織を対象とした各種細胞タイプの選別、in vitroでのがん化誘導による神経芽腫の起源となる細胞(がん化する細胞タイプ)の同定、網羅的な遺伝子発現解析や介入実験を行い、神経芽腫の時期や細胞特異性に着目した発生機構の解明を目的とする。

  2. Mechanism of neuroblastoma development caused by epigenetic abnormalities induced by MYCN and EZH2

    Grant number:20K16355  2020.4 - 2022.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Tsubota Shoma

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    Authorship:Principal investigator 

    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    Neuroblastoma is a childhood cancer and caused by MYCN, a well-known oncogene. We have been working to elucidate the mechanism of oncogenesis by MYCN and the epigenomic regulator EZH2. In this study, we could not reproduce the previous report that the MB2 domain of MYCN is bound to EZH2. However, we obtained data suggesting that the MB2 domain may be essential for the transforming ability of MYCN. In addition, MYCN and EZH2 co-localized at the promoter sites of MYCN target genes in the genome, suggesting the existence of a new regulatory mechanism for gene expression by MYCN and EZH2.

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  3. Mechanism of neuroblastoma development by MYCN-PRC2 mediated epigenomic aberrations

    Grant number:18K15208  2018.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Tsubota Shoma

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    Neuroblastoma is a childhood cancer, and is caused by the well-known oncogene, MYCN. The applicant previously reported that EZH2, an epigenomic regulator, is important for MYCN-induced neuroblastoma development, that MYCN binds to EZH2, and that inhibition EZH2 function can prevent neuroblastoma growth. In this study, we investigated whether the binding of MYCN to EZH2 is essential for the development of neuroblastoma. Unfortunately, we could not reproduce the previous report that a part of MYCN is required for the binding of EZH2 in the first place, so we did not achieve our goal within the study period.

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  4. MYCN-Tgマウスにおける神経芽腫発生の運命決定機構の解明

    Grant number:14J00157  2014.4 - 2017.3

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    坪田 庄真

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    本研究は、小児がんの一つである神経芽腫のMYCN-Tgマウスモデルにおける腫瘍発生の運命決定機構の解明である。特に腫瘍形成初期イベントに着目し、MYCN-Tgマウスの組織とSpheroid cultureによって得られた細胞を対象に網羅的解析を行い、エピゲノム制御分子であるPRC2 が神経芽腫の発生初期において重要な分子の一つであることを明らかにした。PRC2の中でもヒストンメチル基転移酵素のEzh2が、ヒストンH3の27番目のリジンをトリメチル化(H3K27me3)しターゲット分子の発現を抑制する。
    MYCN-Tg由来Sphereでは野生型由来Sphereに比べ、PRC2ターゲット遺伝子の発現が低下していた。ゲノムレベルでのH3K27me3修飾状態を調べるためにChIP-sequencingを行った。その結果、MYCN-Tg由来SphereではPRC2ターゲット分子の遺伝子領域(特にプロモーター)でH3K27me3が増加していた。PRC2ターゲット遺伝子の発現低下が、H3K27me3レベルの増加によるものであることが示唆された。
    Ezh2に対するshRNAとそのヒストンメチル基転移活性を阻害する薬を用い介入実験を行った。その結果、ノックダウン及び薬のどちらもin vitroでの細胞増殖を著しく抑制した。また、阻害剤はin vivoにおいてもTH-MYCNマウスの腫瘍形成を著しく阻害した。神経芽腫においてEzh2がその生存に必須であることを示唆している。
    最後に、約500例のヒト神経芽腫の発現解析データを調べた結果、より悪性度が高い患者でPRC2ターゲットの発現が低く、予後不良と相関していることが明らかになった。
    これまで神経芽腫におけるPRC2の役割、特に腫瘍発生の初期に関わっているという報告はなく、新規な知見を得ることができた。

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