Mechanisms of carcinogenesis through deviation from normal development

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15079
• Research Institution: Nagoya University
• Principal Investigator: 門松 健治 名古屋大学, 医学系研究科, 教授 (80204519)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 癌 / 発生・分化

Outline of Annual Research Achievements

小児がんは遺伝子変異が極めて少ない。何故、遺伝子変異がないのにがんになるのか？この課題に迫るために、私たちはがん発生初期を捉える新しい技術開発を行い、がん発生極初期の細胞のスフェア培養に成功した。これにより、神経芽腫モデルでは、がん化が組織学的に明らかでない胎児期中期に、がん形質の獲得が起こることを見出した。以上を基盤に小児がんの発生機構を解くことが本研究の目的であった。得られた結論は、用いた神経芽腫モデルではエピジェネティックな制御ががん形成に重要であること、EZH2が治療のための優れた分子標的となることであった。
マウス神経芽腫腫瘍スフェア培養法によって、E13.5の時期からMYCN Tgマウス交感神経節からは継代可能なスフェアを培養でき、腫瘍形成能があることを明らかにした。そこで、野生型およびMYCN TgマウスのE13.5交感神経節スフェアについて遺伝子発現アレイを用いた解析を行った。その結果、MYCN下流遺伝子群をはじめ、特徴的な機能を持つ遺伝子群が1.5倍以上の有意な変化を示した。殊にポリコーム抑制複合体2（PRC2）の標的遺伝子の変化が特徴的であった。DNAメチル化をMBDシークエンスで解析すると野生型とMYCN Tgマウスとの間に差を認めた。プロモーター領域のDNAメチル化に焦点を当てて、それを遺伝子発現解析結果と組み合わせると、プロモーター領域のDNAメチル化が起き発現が抑制されている遺伝子の組合せ度数が患者の予後と強く相関することが分かった。一方、E13.5交感神経節スフェアやMYCN Tgマウス腫瘍などを材料にゲノム変化をアレイCGH、エクソームシークエンスで解析したところ、ゲノムレベルの異常はほとんど見られず、この結果もヒト神経芽腫のデータと合致した。さらに、PRC2の中核分子EZH2の阻害剤を用いるとMYCN Tgマウスの腫瘍形成を著しく抑えた。

Research Products

• [Journal Article] Correction of spherical aberration in multi-focal multiphoton microscopy with spatial light modulator. (2017)
  • Author(s): Matsumoto N, Konno A, Ohbayashi Y, Inoue T, Matsumoto A, Uchimura K, Kadomatsu K, Okazaki S.
  • Journal Title: Opt Express. Volume: 25(6) Pages: 7055-7068.
  • DOI: 10.1364/OE.25.007055.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology. (2017)
  • Author(s): Zhang Z, Takeda-Uchimura Y, Foyez T, Ohtake-Niimi S, Narentuya, Akatsu H, Nishitsuji K, Michikawa M, Wyss-Coray T, Kadomatsu K, Uchimura K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(14) Pages: E2947-E2954.
  • DOI: 10.1073/pnas.1615036114.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system. (2017)
  • Author(s): Yoshimura T, Hayashi A, Handa-Narumi M, Yagi H, Ohno N, Koike T, Yamaguchi Y, Uchimura K, Kadomatsu K, Sedzik J, Kitamura K, Kato K, Trapp BD, Baba H, Ikenaka K.
  • Journal Title: Sci Rep. Volume: 7 Pages: 42257.
  • DOI: 10.1038/srep42257.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis. (2017)
  • Author(s): Masuda T, Maeda K, Sato W, Kosugi T, Sato Y, Kojima H, Kato N, Ishimoto T, Tsuboi N, Uchimura K, Yuzawa Y, Maruyama S, Kadomatsu K.
  • Journal Title: Am J Pathol. Volume: 187(4) Pages: 740-751.
  • DOI: 10.1016/j.ajpath.2016.12.006.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): Development of a "TRAP" to increase levels of TIMP-3 in the tissue. (2017)
  • Author(s): Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Muller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K.
  • Journal Title: Matrix Biol. Volume: 59 Pages: 69-79.
  • DOI: 10.1016/j.matbio.2016.07.004.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Nogo receptor 1 is expressed in both primary cultured glial cells and neurons. (2016)
  • Author(s): Ukai J, Imagama S, Ohgomori T, Ito Z, Ando K, Ishiguro N, Kadomatsu K.
  • Journal Title: Nagoya J Med Sci. Volume: 78(3) Pages: 303-311.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduced molecular size and altered disaccharide composition of cerebral chondroitin sulfate upon Alzheimer's pathogenesis in mice. (2016)
  • Author(s): Zhang Z, Ohtake-Niimi S, Kadomatsu K, Uchimura K.
  • Journal Title: Nagoya J Med Sci. Volume: 78(3) Pages: 293-301.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SGO1 is involved in the DNA damage response in MYCN-amplified neuroblastoma cells. (2016)
  • Author(s): Murakami-Tonami Y, Ikeda H, Yamagishi R, Inayoshi M, Inagaki S, Kishida S, Komata Y, Jan Koster, Takeuchi I, Kondo Y, Maeda T, Sekido Y, Murakami H, Kadomatsu K.
  • Journal Title: Sci Rep. Volume: 6 Pages: 31615.
  • DOI: 10.1038/srep31615.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Midkine Deteriorates Cardiac Remodeling via Epidermal Growth Factor Receptor Signaling in Chronic Kidney Disease. (2016)
  • Author(s): Honda Y, Shishido T, Takahashi T, Watanabe T, Netsu S, Kinoshita D, Narumi T, Kadowaki S, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Kishida S, Kadomatsu K, Takeishi Y, Kubota I.
  • Journal Title: Hypertension. Volume: 67(5) Pages: 857-865.
  • DOI: 10.1161/HYPERTENSIONAHA.115.06922.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Comparative morphometric analysis of microglia in the spinal cord of SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis. (2016)
  • Author(s): Ohgomori T, Yamada J, Takeuchi H, Kadomatsu K, Jinno S.
  • Journal Title: Eur J Neurosci. Volume: 43(10) Pages: 1340-1351.
  • DOI: 10.1111/ejn.13227.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice. (2016)
  • Author(s): Suzuki K, Satoh K, Ikeda S, Sunamura S, Otsuki T, Satoh T, Kikuchi N, Omura J, Kurosawa R, Nogi M, Numano K, Sugimura K, Aoki T, Tatebe S, Miyata S, Mukherjee R, Spinale FG, Kadomatsu K, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 36(4) Pages: 636-646.
  • DOI: 10.1161/ATVBAHA.115.306686.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Keratan Sulfate Regulates the Switch from Motor Neuron to Oligodendrocyte Generation During Development of the Mouse Spinal Cord. (2016)
  • Author(s): Hashimoto H, Ishino Y, Jiang W, Yoshimura T, Takeda-Uchimura Y, Uchimura K, Kadomatsu K, Ikenaka K.
  • Journal Title: Neurochem Res. Volume: 41(1-2) Pages: 450-462.
  • DOI: 10.1007/s11064-016-1861-9.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Sulfated glycans regulate autophagy and axon regenetation (2016)
  • Author(s): Kenji Kadomatsu
  • Organizer: SfN-Neuroscience2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research / Invited
• [Presentation] マスタープランの現状についてー統合的生命科学研究推進プラットフォームー (2016)
  • Author(s): 門松健治
  • Organizer: 第14回 糖鎖科学コンソーシアムシンポジウム
  • Place of Presentation: ソラシティ コンファレンスセンター（東京お茶の水、東京都千代田区）
  • Year and Date: 2016-11-01 – 2016-11-02
  • Invited
• [Presentation] Mechanisms of axon regeneration inhibition after neuronal injury (2016)
  • Author(s): Kenji Kadomatsu
  • Organizer: Freiburg/Adelaide/Nagoya Annual Symposium
  • Place of Presentation: The University of Adelaide, Australia
  • Year and Date: 2016-10-17 – 2016-10-18
  • Int'l Joint Research / Invited
• [Presentation] 硫酸化糖鎖によるオートファジーと軸索再生の制御 (2016)
  • Author(s): 門松健治
  • Organizer: 第57回 日本生化学会 中国・四国支部例会
  • Place of Presentation: 高知大学 岡豊キャンパス（高知県南国市）
  • Year and Date: 2016-05-27 – 2016-05-28
  • Invited
• [Presentation] Mechanisms of Axon Regeneration and its Inhibition. (2016)
  • Author(s): Kenji Kadomatsu
  • Organizer: Fourth Midkine Symposium
  • Place of Presentation: Budapest, Hungary (Hungarian Institution of Foreign Affairs & Trade)
  • Year and Date: 2016-04-28 – 2016-04-30
  • Int'l Joint Research / Invited