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胆肝癌とその幹細胞の悪性分化に関わる新規糖鎖修飾蛋白質の同定と構造機能の解析

Research Project

Project/Area Number 14F04099
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Research Field Tumor biology
Research InstitutionKumamoto University

Principal Investigator

荒木 令江  熊本大学, 大学院生命科学研究部(医), 准教授 (80253722)

Co-Investigator(Kenkyū-buntansha) SILSIRIVANIT ATIT  熊本大学, 大学院生命科学研究部(医), 外国人特別研究員
SILSIRIVANIT Atit  熊本大学, 大学院生命科学研究部, 外国人特別研究員
Project Period (FY) 2014-04-25 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2015: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2014: ¥1,200,000 (Direct Cost: ¥1,200,000)
KeywordsCancer Stem Cell / cholangiocarcinoma / glyco-proteomics / 胆管癌 / グライコミクス / 癌幹細胞
Outline of Annual Research Achievements

胆肝癌(CCA)は、最も予後が悪い悪性腫瘍である。近年、がん幹細胞の概念が導入され、CCAにおいてもこれらの存在が示唆され、これを用いたCCA悪性化メカニズムの解明が期待されている。本研究では、CCAとCCA幹細胞を中心に、悪性腫瘍分化に関わる特異的糖蛋白質の同定と、その修飾構造の詳細な構造解析、およびその生物学的意義を解析した。まず、患者組織から確立されたCCA培養細胞の脱分化モデルの樹立を行った。幹細胞培地にてCCA細胞を長期培養したところ、最も未分化とされるM055CCA細胞においてsphere状の幹細胞様変化が観察され、FCSを添加することによって、再分化することが判明した。sphere状態で培養を続け、20回目の継代培養を経た細胞において各種マーカー類の解析を行ったところ、sphere状態のCCAにはSox2をはじめとする幹細胞マーカー群、およびo-GlcNacylation修飾タンパク質(OGP)の発現が亢進する事が判明した。同時進行で樹立を行ったGlioma幹細胞についても同様にo-GlcNacylationの顕著な増加が観察された。そこで、o-GlcNacylationに関わる酵素GFAT阻害剤6-Diazo-5-oxo-L-norleucineおよび活性化剤Glutamine/N-Acetyl Glucosamineの処理をおこなったところ、前者においては幹細胞形成阻害が、また後者においては分化誘導阻害が顕著であることが判明した。さらに、修飾分子の同定をClick-IT®-GlcNAz法を用いた質量分析によって行い、現在までに幹細胞形成に重要な23種のOGPの同定に成功している。興味深いことにこれらには転写や染色体リモデリングの関連分子が多く含まれており、現在詳細な検証実験を行っている。がん幹細胞モデルにおいて、o-GlcNacylationが悪性分化に関わる分子発現の調節に関わっており、修飾タンパク質や責任酵素の阻害剤ががん幹細胞による悪性分化の阻害に有効である可能性が示唆された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (41 results)

All 2016 2015 2014 Other

All Int'l Joint Research (1 results) Journal Article (12 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (25 results) (of which Int'l Joint Research: 4 results,  Invited: 13 results) Book (2 results) Remarks (1 results)

  • [Int'l Joint Research] Khon Kaen University(Thailand)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] YKL-40/chitinase-3-like protein 1 is associated with poor prognosis and promotes cell growth and migration of cholangiocarcinoma.2016

    • Author(s)
      Thongsom S, Chaocharoen W, Silsirivanit A, Wongkham S, Sripa B, Choe H, Suginta W, Talabnin C.
    • Journal Title

      Tumour Biol

      Volume: in press

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer.2016

    • Author(s)
      Izumi D, Ishimoto T, Miyake K, Sugihara H, Eto K, Sawayama H, Yasuda T, Kiyozumi Y, Kaida T, Kurashige J, Imamura Y, Hiyoshi Y, Iwatsuki M, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Takamori H, Araki N, Tan P, Baba H.
    • Journal Title

      Int J Cancer

      Volume: 1;138(5) Issue: 5 Pages: 1207-19

    • DOI

      10.1002/ijc.29864

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A Promising Serum Autoantibody Marker, Anti-Heat Shock Protein 90α, for Cholangiocarcinoma.2015

    • Author(s)
      Boonjaraspinyo S, Juasook A, Boonmars T, Aukkanimart R, Silsirivanit A, Loilome W, Sriraj P, Wu Z, Ratanasuwan P.
    • Journal Title

      Asian Pac J Cancer Prev

      Volume: 16(14) Pages: 5779-5785

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effects of GUASHA on Heart Rate Variability in Healthy Male Volunteers under Normal Condition and Weightlifters after Weightlifting Training Sessions.2015

    • Author(s)
      Wang X, Chatchawan U, Nakmareong S, Silsirivanit A, Wang Y, Xie D, Yang J, Eungpinichpong W.
    • Journal Title

      Evid Based Complement Alternat Med.

      Volume: 268471 Pages: 268471-268471

    • DOI

      10.1155/2015/268471

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Improve discrimination power of serum markers for diagnosis of cholangiocarcinoma using data mining-based approach.2015

    • Author(s)
      Pattanapairoj S, Silsirivanit A, Muisuk K, Seubwai W, Cha'on U, Vaeteewoottacharn K, Sawanyawisuth K, Chetchotsak D, Wongkham S.
    • Journal Title

      Clin Biochem.

      Volume: in press Issue: 10-11 Pages: 668-673

    • DOI

      10.1016/j.clinbiochem.2015.03.022

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Novel mutations in cholangiocarcinoma with low frequencies revealed by whole mitochondrial genome sequencing.2015

    • Author(s)
      Muisuk K, Silsirivanit A, Imtawil K, Bunthot S, Pukhem A, Pairojkul C, Wongkham S, Wongkham C.
    • Journal Title

      Asian Pac J Cancer Prev.

      Volume: 16(5) Pages: 1737-1742

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Up-regulation of DRP-3 long isoform during the induction of neural progenitor cells by glutamate treatment in the ex vivo rat retina.2015

    • Author(s)
      Tokuda K, Kuramitsu Y, Byron B, Kitagawa T, Tokuda N, Kobayashi D, Nagayama M, Araki N, Sonoda K , Nakamura K.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 463 Issue: 4 Pages: 593-599

    • DOI

      10.1016/j.bbrc.2015.05.102

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel mutations in cholangiocarcinoma with low frequencies revealed by whole mitochondrial genome sequencing2015

    • Author(s)
      Muisuk K, Silsirivanit A, Imtawil K, Bunthot S, Pukhem A, Pairojkul C, Wongkham S, Wongkham C
    • Journal Title

      Asian Pac J Cancer Prev.

      Volume: 16(5) Pages: 1737-42

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2014 Annual Research Report
    • 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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of a fully automated two-dimensional electrophoresis device, Auto-2D, and its application for the integrated proteomics2014

    • Author(s)
      Araki N, Niibori NA, Nishimura M, Midorikawa U, Kobayashi D.
    • Journal Title

      Japanese J. Electrophoresis

      Volume: 58(2) Pages: 39-42

    • NAID

      130004704682

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Presentation] プロテオミクスを基盤とした統合オミクスによるがん組織細胞の異常シグナルネットワークの抽出と検証2015

    • Author(s)
      荒木 令江 、南部-新堀 晶子 、シルシリバニト アチト 、小林 大樹
    • Organizer
      BMB2015 (第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
    • Place of Presentation
      神戸ポートアイランド(神戸)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Interactome analysis identified a novel interaction form of TCTP and translation elongation factors in Neurofibromatosis-type 1-associated tumors.2015

    • Author(s)
      小林 大樹 、徳田 高穂 、長山 慈 、平山 未央 、大槻 純男 、荒木 令江
    • Organizer
      BMB2015 (第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
    • Place of Presentation
      神戸ポートアイランド(神戸)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Dynamic changes of O-GlcNAcyaltion in glioma stem cells.2015

    • Author(s)
      Silsirivanit A, Nambu A, Yamasaki Y, Nagai M, Nagayama M, Kobayashi D, Araki N
    • Organizer
      7th Asian Community of Glycoscience and Glycotechnology Conference
    • Place of Presentation
      Hotel Taikanso, Miyagi (Japan)
    • Year and Date
      2015-11-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] The anti-metastatic activity of chloroquine on cholangiocarcinoma cell lines2015

    • Author(s)
      Diwakar Guragain, Wunchana Seubwai, Atit Silsirivanit, Sumalee Obchoei, Sopit Wongkham, Norie Araki, Ubon Chaon
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋市国際会議場(名古屋)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] Comparative proteomics of cholangiocarcinoma cell lines, KKU-M214 and KKU-M214L5 with different metastatic potentials2015

    • Author(s)
      Waraporn Saentaweesuk, Atit Silsirivanit, Kulthida Vaeteewoottacharn, Sopit Wongkham, Chaisiri Wongkham, Norie Araki
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋市国際会議場(名古屋)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] O-GlcNAcylation regulates the stemness-maintenance of glioma stem cells2015

    • Author(s)
      Atit Silsirivanit, Akiko Niibori-Nambu, Minako Nagai, Megumi Nagayama, Norie Araki
    • Organizer
      第74回日本癌学会学術総会
    • Place of Presentation
      名古屋市国際会議場(名古屋)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Annual Research Report
  • [Presentation] Functional Characterization of a Novel NF1-Related Protein TCTP by the Interactome Analysis2015

    • Author(s)
      Daiki Kobayashi , Takaho Tokuda , Megumi Nagayama , Mio Hirayama , Sumio Ohtsuki , Norie Araki
    • Organizer
      HUPO2015
    • Place of Presentation
      Vancouver Convention Centre (Canada)
    • Year and Date
      2015-09-27
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Integrated Proteomics for Identification of the Specific Network in Cancer Stem Cells2015

    • Author(s)
      Norie Araki , Akiko Niibori-Nambu , Atit Silsirivanit , Daiki Kobayashi
    • Organizer
      HUPO2015
    • Place of Presentation
      Vancouver Convention Centre (Canada)
    • Year and Date
      2015-09-27
    • Related Report
      2015 Annual Research Report
  • [Presentation] 融合プロテオミクスを用いたグリオーマ幹細胞の分化・維持に関わる糖タンパク質の同定2015

    • Author(s)
      荒木 令江
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] プロテオミクスデータの細胞生物学的な検証法2015

    • Author(s)
      小林大樹、荒木令江
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] High glucose condition enhances aggressive phenotypes of cholangiocarcinoma2015

    • Author(s)
      Sopit Wongkham, Charupong Saengboonmee, Chatchai Phoomak, Wunchana Seubwai, Kulthida Vaeteewoottachar, Atit Silsirivanit, Chaisiri Wongkham
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Cholangiocarcinoma cell line; KKU-M214L5 and its parental; KKU-M214 revealed by a label-free proteomic analysis2015

    • Author(s)
      Waraporn Saentaweesuk , Atit Silsirivanit , Kulthida Vaeteewoottacha , Sopit Wongkham , Norie Araki , Chaisiri Wongkha
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
  • [Presentation] Functional analysis of chloroquine toxicity2015

    • Author(s)
      Diwakar Guragain, Atit Silsirivanit , Wunchana Seubwai, Sopit Wongkham , Ubon Cha’on, Akira Sasao, Ako Sasao, Norie Araki
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
  • [Presentation] Cancer stem cells up-regulate O-GlcNAcylation systems to maintain their stemness2015

    • Author(s)
      Atit Silsirivanit, Akiko Nambu , Yoshimune Yamasaki , Minako Nagai , Megumi Nagayama ,Daiki Kobayashi , Norie Araki
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
  • [Presentation] 融合プロテオミクスのデータ統合ツールiPEACH によるグリオーマ幹細胞の維持と分化に関わるネットワーク解析2015

    • Author(s)
      山崎 義宗 、南部 晶子 、吉沢 明康 、水口 惣平 、小林 大樹 、長山 慈 、永井 美奈子 、Atit Silsirivanit 、河野 信 、佛淵 尚人 、荒木 令江
    • Organizer
      日本プロテオーム学会2015年会
    • Place of Presentation
      熊本森都市プラザ(熊本)
    • Year and Date
      2015-07-22
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 融合プロテオミクスによるがん幹細胞とニッチ標的分子群の解析2015

    • Author(s)
      荒木 令江
    • Organizer
      第11回日本臨床プロテオーム研究会
    • Place of Presentation
      国立がん研究センター(東京)
    • Year and Date
      2015-05-23
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 融合プロテオミクスによるがん幹細胞の異常シグナルネットワークの解析2015

    • Author(s)
      小林大樹、荒木令江
    • Organizer
      第11回日本臨床プロテオーム研究会
    • Place of Presentation
      国立がん研究センター(東京)
    • Year and Date
      2015-05-23
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Integrated proteomics for identification of specific targets in cancer stem cells2015

    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Development of a fully automated two-dimensional electrophoresis device, Auto-2D, and its application for the integrated proteomics2014

    • Author(s)
      Norie Araki, Akiko Nambu, Uichi Midorikawa, Souhei Mizuguchi, Daiki Kobayashi, Jun-ichi Kuratsu
    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Integrated Proteomics for Cancer Stem Cells2014

    • 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
    • Related Report
      2014 Annual Research Report
  • [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 – 2014-09-28
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] CA-S27: a novel Lewis a associated carbohydrate epitope is diagnostic and prognostic for cholangiocarcinoma2014

    • 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.
    • 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
    • Related Report
      2014 Annual Research Report
    • 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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ALTERATION OF PROTEIN GLYCOSYLATION AS BIOMARKERS FOR CHOLANGIOCARCINOMA2014

    • Author(s)
      Atit Silsirivanit, Chatchai Phoomak, , Somsiri Indramanee, , Lukkana Sukprasert, Waraporn Saentaweesuk, Anucha Puapairoj, Chawalit Pairojkul, Chaisiri Wongkham, Araki Norie, Sopit Wongkham
    • 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
    • Related Report
      2014 Annual Research Report
  • [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
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Book] 臨床プロテオミクス 医学のあゆみ別冊2016

    • Author(s)
      荒木令江, 南部(新堀)晶子, 小林大樹
    • Publisher
      医歯薬出版
    • Related Report
      2015 Annual Research Report
  • [Book] The frontier of proteomics-based life science and its clinical application.2015

    • Author(s)
      荒木令江 他
    • Total Pages
      260
    • Publisher
      Japan Proteome Society
    • Related Report
      2015 Annual Research Report
  • [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

    • Related Report
      2014 Annual Research Report

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Published: 2015-01-22   Modified: 2024-03-26  

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