Systemic analysis of metabolic reprogramming of live cancer stem cells

• Project/Area Number: 16K19378
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Qin Xian-Yang 国立研究開発法人理化学研究所, ライフサイエンス技術基盤研究センター, 特別研究員 (60756815)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 不飽和脂肪酸 / がん幹細胞 / 肝発がん / MYCN / オミクス解析 / 酸化ストレス / 肝癌 / 癌幹細胞 / 化学予防 / 癌 / 細胞・組織 / 発生・分化 / 脂質 / シグナル伝達

Outline of Final Research Achievements

Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of hepatocellular carcinoma (HCC). I performed omics analyses to identify molecular targets of ACR. In vivo metabolome analysis revealed that inhibition of biosynthesis of unsaturated fatty acids such as arachidonic acid (AA) but not glucose metabolism played a crucial role in the prevention of hepatic tumorigenesis by ACR. In vitro mechanical analysis showed a critical role of induced ROS/TG2 signaling in liver injury by AA. A genome-wide transcriptome analysis identified that an MYCN+EpCAM+ cancer stem cell (CSC)-like subpopulation was selectively depleted by ACR. Further proteome/metabolome analyses showed unsaturated fatty acids were enriched in EpCAM+ CSC-like HCC cells compared with EpCAM- cells. These findings suggested a potential role of unsaturated fatty acid-associated metabolic changes during hepatic tumorigenesis, which might serve as a therapeutic target for HCC prevention.

Research Products

• [Int'l Joint Research] Ohio State University(米国)
• [Int'l Joint Research] CNRIFFI(中国)
• [Int'l Joint Research] Ohio State University(米国)
• [Journal Article] Prevention of hepatocellular carcinoma by targeting MYCN-positive liver cancer stem cells with acyclic retinoid (2018)
  • Author(s): Qin XY, Suzuki H, Honda M, Okada H, Kaneko S, Inoue I, Ebisui E, Hashimoto K, Carninci P, Kanki K, Tatsukawa H, Ishibashi N, Masaki T, Matsuura T, Kagechika H, Toriguchi K, Hatano E, Shirakami Y, Shiota G, Shimizu M, Moriwaki H, Kojima S
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 19 Pages: 4969-4974
  • DOI: 10.1073/pnas.1802279115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptome Analysis Uncovers a Growth-Promoting Activity of Orosomucoid-1 on Hepatocytes (2017)
  • Author(s): Qin Xian-Yang et al.
  • Journal Title: EBioMedicine Volume: 24 Pages: 257-266
  • DOI: 10.1016/j.ebiom.2017.09.008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Selective depletion of liver cancer stem cells by retinoids (2018)
  • Author(s): Xian-Yang Qin, Soichi Kojima
  • Organizer: JSPS Core-to-core Program Symposium
  • Int'l Joint Research / Invited
• [Presentation] 肝再生時の新しい肝細胞増殖マーカーリポカリンファミリー分子オロソムコイド1 (2017)
  • Author(s): 秦 咸陽、原 詳子、河口 義邦、古谷 裕、永妻 啓介、松浦 知和、國土 典宏、小嶋 聡一
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] Role of transglutaminase 2 in selective deletion of MYCN+CD133+ liver cancer stem cells by acyclic retinoid (2017)
  • Author(s): Xian-Yang Qin, Rajan Shrestha, Sanae Sekihara, Akimori Wada, Soichi Kojima
  • Organizer: Debrecen University Symposium TGase
  • Int'l Joint Research
• [Presentation] 非環式レチノイドによる肝癌化学予防の分子機構解明に向けた網羅的解析の取り込み (2017)
  • Author(s): 秦 咸陽、小嶋 聡一
  • Organizer: 第28回日本レチノイド研究会学術集会
  • Invited
• [Presentation] Hepatic orosomucoid is an additional essential regulator promoting hepatocyte proliferation during liver regeneration (2016)
  • Author(s): Xian-Yang Qin, Mitsuko Hara, Erik Arner, Yoshikuni Kawaguchi, Norihiro Kokudo, Harukazu Suzuki, Piero Carninci, Alistair Forrest, Soichi Kojima
  • Organizer: AASLD2016 第67回米国肝臓学会議
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center (Boston, MA, USA)
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] ベイジアンネットワーク解析を用いた肝再生調節因子の探索 (2016)
  • Author(s): 秦咸陽
  • Organizer: 情報計算化学生物学会CBI学会2016年大会
  • Place of Presentation: タワーホール船堀（東京都・江戸川区）
  • Year and Date: 2016-10-27
  • Invited
• [Presentation] リポカリンファミリー分子による肝細胞増殖の制御 (2016)
  • Author(s): 秦咸陽、原詳子、小嶋聡一
  • Organizer: 第27回日本レチノイド研究会学術集会
  • Place of Presentation: 昭和薬科大学（東京都・町田市）
  • Year and Date: 2016-10-22
• [Presentation] トランスクリプト－ム解析からわかった肝類洞内皮細胞と肝細胞の相互作用による新規肝再生制御因子リポカリンOrm1の同定 (2016)
  • Author(s): 秦咸陽、原詳子、鈴木治和、小嶋聡一
  • Organizer: 第23回肝細胞研究会報告
  • Place of Presentation: 大阪大学中之島センター（大阪府・大阪市）
  • Year and Date: 2016-07-07
• [Presentation] Acyclic retinoid inhibits aberrant lipogenesis to prevent diethylnitrosamine-induced hepatic tumorigenesis (2016)
  • Author(s): Xian-Yang Qin, Yohei Shirakami, Naoto Ishibashi, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima
  • Organizer: FASEB's 3rd International Conference on Retinoids
  • Place of Presentation: Marriott West Palm Beach (West Palm Beach, FL, USA)
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] 脂質代謝を標的とした非環式レチノイドによる肝発癌の化学予防 (2016)
  • Author(s): 秦咸陽、白上洋平、石橋直人、清水雅仁、森脇久隆、小嶋聡一
  • Organizer: 日本ケミカルバイオロジー学会 第11回年会
  • Place of Presentation: 京都テルサ（京都府・京都市）
  • Year and Date: 2016-06-17
• [Presentation] 新規肝（癌）細胞増殖因子リポカリンOrm1 (2016)
  • Author(s): 秦咸陽、小嶋聡一
  • Organizer: 第20回日本がん分子標的治療学会学術集会
  • Place of Presentation: 別府国際コンベンションセンター（大分県・別府市）
  • Year and Date: 2016-05-31
• [Presentation] 網羅解析による非環式レチノイドの肝癌再発化学予防標的シグナルの同定 (2016)
  • Author(s): 秦 咸陽、Shrestha Rajan、小嶋 聡一
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張（千葉県・千葉市）
  • Year and Date: 2016-05-19
• [Remarks] Vitamin A derivative selectively kills liver CSCs
  • URL: http://www.riken.jp/en/pr/press/2018/20180424_1/
• [Remarks] 非環式レチノイドによるMYCN陽性肝がん幹細胞の排除
  • URL: http://www.riken.jp/pr/press/2018/20180424_1/
• [Remarks] 肝細胞の増殖を促進する肝再生制御因子Orm1
  • URL: http://www.riken.jp/pr/press/2017/20171024_3/