Analysis of molecular network on maintenance and differentiation of glioma stem cells

• Project/Area Number: 25640068
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kumamoto University
• Principal Investigator: ARAKI Norie 熊本大学, その他の研究科, 准教授 (80253722)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: がん幹細胞 / プロテオミクス / 分子治療標的 / グリオーマ幹細胞 / 融合プロテオミクス / mTOR / 幹細胞

Outline of Final Research Achievements

To identify the molecular network regulating the maintenance/differentiation of glioma stem cells (GSCs), we established 9 clones from patient’s gliomas having the potential to form glioblastomas, and subjected to iTRAQ, 2D-DIGE and DNA array based integrated proteomics. iPEACH analysis of 8,471 proteins and 21,857 mRNAs revealed that ECMs-integrins-RAS-MAPK/PI3K signalings were significantly upregulated during GSC differentiation. The differentiation was dramatically accelerated by the ligand ECMs, and suppressed by integrin inhibitors that raised GSC chemosensitivity. Combination of TMZ and their inhibitors suppressed glioma progression and led the longer survival of mouse xenograft models. These results demonstrate that GSCs induce ECMs/receptors-related network to regulate their stemness and differentiation process via developing specific niches. This is the first integrated proteomics providing new therapeutic ideas against the stem cell-associated malignant gliomas.

Research Products

• [Journal Article] TogoTable: cross-database annotation system using the Resource Description Framework (RDF) data model. (2014)
  • Author(s): Kawano S, Watanabe T, Mizuguchi S, Araki N, Katayama T and Yamaguchi A.
  • Journal Title: Nucleic Acids Resarch Volume: 42 Issue: W1 Pages: W442-W448
  • DOI: 10.1093/nar/gku403
  • Peer Reviewed / Open Access
• [Journal Article] Translationally Controlled Tumor Protein is a Novel Biological Target for Neurofibromatosis Type 1 (NF1)-associated Tumors. (2014)
  • Author(s): Kobayashi, D., Hirayama M., Komohara, Y., Mizuguchi, S, Wilson Morifuji, M. Patrakitkomjorn, S, Ihn, H., Takeya, M, Kuramochi, A., and Araki, N*.
  • Journal Title: J. Biol. Chem. Volume: 289(38) Issue: 38 Pages: 26314-26
  • DOI: 10.1074/jbc.m114.568253
  • Peer Reviewed / Open Access
• [Journal Article] Development of a fully automated two-dimensional electrophoresis device, Auto-2D, and its application for the integrated proteomics (2014)
  • Author(s): 荒木令江*, 南部（新堀 晶子）晶子, 西村宗総、緑川 宇一, 小林大樹
  • Journal Title: 生物物理化学 Volume: 58(2) Pages: 39-42
  • NAID: 130004704682
• [Journal Article] 融合プロテオミクスによるは発がんメカニズムの解析 (2014)
  • Author(s): 荒木令江*, 南部（新堀 晶子）晶子, 小林大樹
  • Journal Title: 医学のあゆみ Volume: 251(10) Pages: 939-947
• [Journal Article] Integrated proteomics identified novel activation of dynein IC2-GR-COX-1 signaling in NF1 disease model cells. (2013)
  • Author(s): Hirayama M, Kobayashi D, Mizuguchi S, Morikawa T, Nagayama M, Midorikawa U, Wilson MM, Nambu AN, Yoshizawa AC, Kawano S, Araki N.
  • Journal Title: Molecular & Cellular Proteomics Volume: 28 Issue: 5 Pages: 1377-94
  • DOI: 10.1074/mcp.m112.024802
  • Peer Reviewed
• [Journal Article] Glioma Initiating Cells Form a Differentiation Niche Via the Induction of Extracellular Matrices and Integrin aV (2013)
  • Author(s): Akiko Niibori-Nambu, Uichi Midorikawa, Souhei Mizuguchi, Takuichiro Hide, Minako Nagai,Yoshihiro Komohara, Megumi Nagayama, Mio Hirayama, Daiki Kobayashi, Nobuyuki Tsubota,Tatsuya Takezaki, Keishi Makino, Hideo Nakamura, Motohiro Takeya, Junichi Kuratsu, Norie Araki
  • Journal Title: PLoS ONE Volume: 8(5) Issue: 5 Pages: e59558-e59558
  • DOI: 10.1371/journal.pone.0059558
  • Peer Reviewed
• [Journal Article] Enhancement of human cancer cell motility and invasiveness by anaphylatoxin C5a via aberrantly expressed C5a-receptor (CD88). (2013)
  • Author(s): Nitta, H. et al.
  • Journal Title: Clinical Cancer Reseach Volume: 19 Issue: 8 Pages: 2004-2013
  • DOI: 10.1158/1078-0432.ccr-12-1204
  • Peer Reviewed
• [Journal Article] CA-S27 : a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma (2013)
  • Author(s): Silsirivanit A, Araki N, Wongkham C, Vaeteewoottacharn K, Pairojkul C, Kuwahara K, Narimatsu Y, Sawaki H, Narimatsu H, Okada S, Sakaguchi N, Wongkham S
  • Journal Title: Cancer Sci Volume: 104 Issue: 10 Pages: 1278-1284
  • DOI: 10.1111/cas.12222
  • Peer Reviewed
• [Journal Article] Integrated view of the human chromosome X-centric proteome project. (2013)
  • Author(s): Yamamoto T, Nakayama K, Hirano H, Tomonaga T, Ishihama Y, Yamada T, Kondo T,Kodera Y, Sato Y, Araki N, Mamitsuka H, Goshima N.
  • Journal Title: J Proteome Res. Volume: 12 Issue: 1 Pages: 58-61
  • DOI: 10.1021/pr300844p
  • Peer Reviewed
• [Journal Article] Epiplakin modifies the motility of the HeLa cells and accumulates at the outer surfaces of 3-D cell clusters. (2013)
  • Author(s): Shimada H, Nambu-Niibori A, Wilson-Morifuji M, Mizuguchi S, Araki N, Sumiyoshi H, Sato M, Mezaki Y, Senoo H, Ishikawa K, Hatano Y, Okamoto O, Fujiwara S
  • Journal Title: J Dermatol Volume: 40 Issue: 4 Pages: 249-58
  • DOI: 10.1111/1346-8138.12076
  • Peer Reviewed
• [Presentation] Integrated proteomics for identification of specific targets in cancer stem cells (2015)
  • Author(s): Norie Araki
  • Organizer: KHUPO (THE KOREAN HUMAN PROTEOME ORGANIZATION) 15TH ANNUAL INTERNATIONAL PROTEOMICS CONFERENCE
  • Place of Presentation: Seoul National University, Seoul, Korea
  • Year and Date: 2015-03-26 – 2015-03-27
  • Invited
• [Presentation] Development of a fully automated two-dimensional electrophoresis device, Auto-2D, and its application for the integrated proteomics (2014)
  • Author(s): Norie Araki
  • Organizer: 日本電気泳動学会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2014-10-21 – 2014-10-22
  • Invited
• [Presentation] 融合プロテオミクス：新規治療標的分子ネットワーク同定のためのマルチオミクス解析基盤 (2014)
  • Author(s): 小林 大樹, 荒木 令江
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Functional proteome analysis of translationally controlled tumor protein (TCTP), a novel Neurofibromatosis type 1 (NF1)-related protein (2014)
  • Author(s): Daiki Kobayashi, Megumi Nagayama, Mio Hirayama, Sumio Ohtsuki, Norie Araki
  • Organizer: 13th human proteome organization World Congress
  • Place of Presentation: IFEMA Madrid Spain
  • Year and Date: 2014-10-05 – 2014-10-08
• [Presentation] Integrated Proteomics for Cancer Stem Cells (2014)
  • Author(s): Norie Araki, Akiko Nambu, Uichi Midorikawa, Souhei Mizuguchi, Daiki Kobayashi, Jun-ichi Kuratsu
  • Organizer: 13th human proteome organization World Congress
  • Place of Presentation: IFEMA Madrid Spain
  • Year and Date: 2014-10-05 – 2014-10-08
• [Presentation] グリオーマ幹細胞の維持と分化に関わるニッチ分子群の融合プロテオミクスによる解析 (2014)
  • Author(s): 荒木令江、南部(新堀) 晶子、緑川宇一、水口惣平、小林大樹、ウイルソン森藤政代、秀拓一郎、中村英夫、倉津純一
  • Organizer: 第73回日本癌学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
  • Invited
• [Presentation] 融合プロテオミクスによるがん標的となる修飾分子群の抽出と機能解析 (2014)
  • Author(s): 荒木令江
  • Organizer: レドックス・ライフイノベーション第170委員会 JHUPOサテライトシンポジウ
  • Place of Presentation: 宮崎 シーガイヤ コンベンションセンター
  • Year and Date: 2014-08-22 – 2014-08-23
  • Invited
• [Presentation] 融合プロテオミクスによる疾患メカニズム解析と 標的分子群の検出 ～がん幹細胞の特異的分子群の解析例から～ (2014)
  • Author(s): 荒木令江
  • Organizer: 日本プロテオーム学会2014年会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2014-07-17 – 2014-07-18
  • Invited
• [Presentation] 融合プロテオミクスによる神経系腫瘍の細胞内特異的タンパク質の解析 (2014)
  • Author(s): 小林大樹・ 荒木令江
  • Organizer: 日本プロテオーム学会2014年会
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2014-07-17 – 2014-07-18
  • Invited
• [Presentation] 融合プロテオミクスによる新規NF1病態関連分子ネットワークの同定 (2014)
  • Author(s): 小林大樹・ 平山未央・ 水口惣平・ 荒木令江
  • Organizer: 第62回質量分析総合討論会
  • Place of Presentation: 大阪府吹田市
  • Year and Date: 2014-05-14 – 2014-05-16
  • Invited
• [Presentation] プロテオミクスを基盤とした病態システムズバイオロジー～がん幹細胞の分化メカニズムへの応用～ (2013)
  • Author(s): 荒木令江
  • Organizer: 岡山大学特別講演
  • Place of Presentation: 岡山大学
  • Invited
• [Presentation] 融合プロテオミクスを基盤とした病態システムズバイオロジーによる癌の治療標的検出への挑戦 (2013)
  • Author(s): 荒木 令江
  • Organizer: 神戸大学特別講演
  • Place of Presentation: 神戸大学
  • Invited
• [Presentation] Integrated proteomics for identifying the specific signal networks regulated by post-translational modifications in cancer and cancer stem cel.ls. (2013)
  • Author(s): 荒木 令江
  • Organizer: ５th ACGG(Asian Commumnications of Glycobiology and Glycotechnology) International Conference.
  • Place of Presentation: タイ コンケン大
  • Invited
• [Presentation] 融合プロテオミクスによるグリオーマ幹細胞の分化遊動機構と治療ターゲット分子の解析 (2013)
  • Author(s): 荒木令江、南部(新堀)晶子、緑川宇一、水口惣平、秀拓一郎、小林大樹、ウィルソン森藤政代、菰原義弘、中村英夫、竹屋元裕、倉津純一.
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] HIF-1 alphaシグナルを介した細胞競合によるヘテロな口腔癌細胞集団の発育機構（Heterogeneous oral cancer development by competition via HIF-1 alpha signal regulation） (2013)
  • Author(s): 森藤 政代（モリフジ マサヨ）、 南部(新堀) 晶子、 小林 大樹、荒木 令江
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] An Integrated Proteomics for Extracting Molecular Target of Malignant Gliomas. (2013)
  • Author(s): Norie Araki, Takashi Morikawa, Souhei Mizuguchi, Daiki Kobayashi, Akiko Niibori Nambu, Uichi Midorikawa, Mio Hirayama, Masayo morifuji Wilson, Sin Kawano, Hideo Nakamura, Junichi Kuratsu.
  • Organizer: HUPO 11th Annual World Congress
  • Place of Presentation: パシフィコ横浜
• [Presentation] Integrated Proteomics for the Study of Metastatic Human Tongue Cancer Development in a heterogeneous Microenvironment (2013)
  • Author(s): Masayo Wilson Morifuji, Akiko Niibori Nambu, daiki kobayashi, Norie Araki.
  • Organizer: HUPO 11th Annual World Congress
  • Place of Presentation: パシフィコ横浜
• [Presentation] Integrated Proteomics for the Study of Metastatic Human Tongue Cancer Development in a heterogeneous Microenvironment. (2013)
  • Author(s): Masayo Wilson Morifuji, Akiko Niibori Nambu, daiki kobayashi, Norie Araki
  • Organizer: HUPO 11th Annual World Congress English oral
  • Place of Presentation: パシフィコ横浜
• [Presentation] Integrated Proteomics Identified Novel Activation of Dynein IC2-GR-COX-1 Signaling by Suppression of NF1 Tumor Suppressor Gene Product, Neurofibromin, in Neuronal Cells.. (2013)
  • Author(s): Daiki Kobayashi, Mio Hirayama, Souhei Mizuguchi Takashi Morikawa, Megumi Nagayama, Uichi Midorikawa, Masayo Wilson-Morifuji, Akiko Nambu-Niibori, Akiyasu Yoshizawa C., Shin Kawano, Norie Araki
  • Organizer: HUPO 11th Annual World Congress
  • Place of Presentation: パシフィコ横浜
• [Presentation] Integrated Proteomics Identified the Akiko Differentination Niche Induced by glioma Stem Cells. (2013)
  • Author(s): Niiboari Nambu, Uichi Midorikawa, Souhei Mizuguchi, Takuichiro Hide, Minako Nagai, Yoshihiro Komohara, Megumi Nagayama, Mio Hirayama, Daiki Kobayashi, Hideo Nakamura, Motohiro Takeya, Jyunichi Kuratsu, Norie Araki.
  • Organizer: HUPO 11th Annual World Congress
  • Place of Presentation: パシフィコ横浜
• [Presentation] A quick profiling System for Cancer marker Proteins with Diverse Post-Translational Modifications by a Fully Automated 2DE Device, Auto-2D. (2013)
  • Author(s): Munenori Nishimura, Uichi Midorikawa, Megumi Nagayama, Daiki Kobayashi, Mio Hirayama, Yoji Murakami, Yoshihiro Wada, Takahisa Imamura, Yutaka Unuma, Norie Araki.
  • Organizer: HUPO 11th Annual World Congress
  • Place of Presentation: パシフィコ横浜
• [Presentation] 融合プロテオミクスによるグリオーマ幹細胞の分化ニッチと悪性化メカニズムの解析. (2013)
  • Author(s): 荒木令江、南部(新堀)晶子、緑川宇一、小林大樹、水口惣平、永井美奈子、秀拓一郎、中村英夫、倉津純一
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 融合プロテオミクスによる神経線維腫症I型（NF1）病態モデル細胞内活性化シグナルDynein IC2-GR-COX-1の同定． (2013)
  • Author(s): 小林大樹、平山未央、水口惣平、森川崇、長山慈、緑川宇一、ウィルソン-森藤政代、南部-新堀晶子、吉沢晶康、河野信、荒木令江.
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 全自動2次元電気泳動装置を用いた前立腺がんマーカータンパク質の解析. (2013)
  • Author(s): 西村宗徳、小林大樹、緑川宇一、長山慈、村上洋嗣、河野吉昭、今村隆寿、和田孝浩、鵜沼豊、荒木令江
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 神経系腫瘍の発症メカニズムと治療ターゲットの融合プロテオミクスによる解析 (2013)
  • Author(s): 荒木 令江
  • Organizer: 宮崎大学医学部脳神経外科学特別講演
  • Place of Presentation: 宮崎大学
  • Invited
• [Presentation] 融合プロテオミクスによるがん細胞およびがん幹細胞の悪性化ネットワーク抽出と治療ターゲットの検索 (2013)
  • Author(s): 荒木 令江
  • Organizer: 第40回BMS (Biological Mass Spectrometry)コンファレンス招待講演
  • Place of Presentation: 宮崎シーガイヤ コンベンションセンター＆シェラトングランデオーシャンリゾート
  • Invited
• [Presentation] 融合プロテオミクスによる異常病態シグナル検出システムの開発と応用 (2013)
  • Author(s): 荒木 令江
  • Organizer: BIO Tech2013 第12回国際バイオテクノロジー展/技術会議
  • Place of Presentation: 東京ビッグサイト
  • Invited
• [Book] プロテオミクス辞典 (2013)
  • Author(s): 荒木令江
  • Total Pages: 127
  • Publisher: 講談社
• [Book] 神経線維腫症2型，皮膚科臨床アセット15 (2013)
  • Author(s): 荒木令江
  • Total Pages: 384
  • Publisher: 中山書店
• [Remarks] 熊本大学大学院生命科学研究部腫瘍医学分野
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/tumor/index.html
• [Remarks] 日本プロテオームデータベースセンター
  • URL: https://www.jhupo.org/database/index.html
• [Remarks] 熊本大学大学院生命科学研究部腫瘍医学分野
  • URL: http://srv02.medic.kumamoto-u.ac.jp/dept/tumor/index.html