Strategy for chemoprevention of digestive cancers by targeting abnormalities in receptor tyrosine kinases and nuclear receptors

• Project/Area Number: 19590720
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gifu University
• Principal Investigator: MORIWAKI Hisataka Gifu University, 大学院・医学系研究科, 教授 (50174470)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Masahito 岐阜大学, 医学部・附属病院, 助教 (90402198) ; YAMADA Yasuhiro 岐阜大学, 大学院・医学系研究科, 講師 (70313872)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2007: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 核内受容体 / 受容体型チロシンキナーゼ / 大腸癌 / 肝臓癌 / レチノイド

Research Abstract

我々は本研究で、受容体型チロシンキナーゼ(RTK)/Ras/MAPKによるレチノイド核内受容体RXRのリン酸化修飾を阻害することで、リン酸化RXRを高発現しているヒト肝癌細胞に、レチノイド依存性に相乗的な増殖抑制効果とアポトーシスの誘導が起こることを明らかにした。今回の研究結果は、RTKやその下流シグナルを阻害し、RXRのリン酸化修飾に伴う機能異常を修復することが、肝発癌予防に結びつく可能性を示唆するものと考えられた。

Research Products

• [Journal Article] Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells (2008)
  • Author(s): Tatebe H, Shimizu M, Shirakami Y, Tsurumi H, Moriwaki H.
  • Journal Title: Clin Cancer Res. 14 Pages: 2806-2812
  • Peer Reviewed
• [Journal Article] EGCG inhibits activation of the insulin-like growth factor(IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells (2008)
  • Author(s): Shimizu M, Shirakami Y, Sakai H, Tatebe H, Nakagawa T, Hara Y, Weinstein IB, Moriwaki H.
  • Journal Title: Cancer Lett. 262 Pages: 10-18
  • Peer Reviewed
• [Journal Article] Retinoid X receptor alpha is highly phosphorylated in retinoic acid-resistant HL-60R cells and the combination of 9-cis retinoic acid plus MEK inhibitor induces apoptosis in the cells (2008)
  • Author(s): Kanemura N, Tsurumi H, Okuno M, Matsushima-Nishiwaki R, Shimizu M, Moriwaki H.
  • Journal Title: Leuk Res. 32 Pages: 884-892
  • Peer Reviewed
• [Journal Article] Synergistic growth inhibition by 9-cis-retinoic acid plustrastuzumab in human hepatocellular carcinoma cells. (2008)
  • Author(s): Tatebe H, et al.
  • Journal Title: Clin Cancer Res 14 Pages: 2806-2812
  • Peer Reviewed
• [Journal Article] EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. (2008)
  • Author(s): Shimizu M, et al.
  • Journal Title: Cancer Lett 262 Pages: 10-18
  • Peer Reviewed
• [Journal Article] Retinoid X receptor alpha is highly phosphorylated in ret inoic acid- resistant HL-60R cells and the combination of 9-cis retinoic acid plus MEK inhibitor induces apoptosis in the cells. (2008)
  • Author(s): Kanemura N, et al.
  • Journal Title: Leuk Res 32 Pages: 884-892
  • Peer Reviewed
• [Journal Article] Synergistic Growth Inhibition by 9-cis-Retinoic Acid Plus Trastuzumab in Human Hepatocellular Carcinoma Cells. (2008)
  • Author(s): Tatebe H
  • Journal Title: Clin Cancer Res 2008(in press)
  • Peer Reviewed
• [Journal Article] EGCG inhibits activation of the insulin-like growth factor(IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. (2008)
  • Author(s): Shimizu M
  • Journal Title: Cancer Lett 262 Pages: 10-18
  • Peer Reviewed
• [Journal Article] Retinoid X receptor alpha is highly phosphorylated in retinoicacid-resistant HL-60R cells and the combination of 9-cis retinoicacid plus MEK inhibitor induces apoptosis in the cells. (2008)
  • Author(s): Kanemura N
  • Journal Title: Leuk Res 32 Pages: 884-892
  • Peer Reviewed
• [Journal Article] Phosphorylated retinoid X receptor α loses its heterodimeric activity with retinoic acid receptor β (2007)
  • Author(s): Yoshimura K, Muto Y, Shimizu M, Matsushima-Nishiwaki R, Okuno M, Takano Y, Tsurumi H, Kojima S, Okano Y, Moriwaki H.
  • Journal Title: Cancer Sci. 98 Pages: 1868-1874
  • NAID: 10019996169
  • Peer Reviewed
• [Journal Article] Chemoprevention of liver carcinogenesis with retinoids : Basic and clinic aspects (2007)
  • Author(s): Moriwaki H, Shimizu M, Okuno M, Nishiwaki-Matsushima R.
  • Journal Title: Hepatol Res. 37(Suppl.2)
  • NAID: 10019773579
  • Peer Reviewed
• [Journal Article] Synergistic effects of RXRα and PPARγ ligands to inhibit growth in human colon cancer cells-phosphorylated RXRα is a critical target for colon cancer management- (2007)
  • Author(s): Yamazaki K, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Kanemura N, Araki H, Tsurumi H, Kojima S, Weinstein IB, Moriwaki H.
  • Journal Title: Gut 56 Pages: 1557-1563
  • Peer Reviewed
• [Journal Article] Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells (2007)
  • Author(s): Kanamori T, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Tsurumi H, Kojima S, Moriwaki H.
  • Journal Title: Cancer Sci. 98 Pages: 431-437
  • Peer Reviewed
• [Journal Article] Granulocyte colony-stimulating factor impairs liver regeneration in mice through the up-regulation of interleukin-1 beta (2007)
  • Author(s): Ogiso T, Nagaki M, Takai S, Tsukada Y, Mukai T, Kimura K, Moriwaki H.
  • Journal Title: J Hepatol 47 Pages: 816-825
  • Peer Reviewed
• [Journal Article] Phosphorylated retinoid X receptor alpha loses its heterodimeriactivity with retinoic acid receptor beta. (2007)
  • Author(s): Yoshimura K
  • Journal Title: Cancer Sci 98 Pages: 1868-1874
  • Peer Reviewed
• [Journal Article] Chemoprevention of liver carcinogenesis with retinoides: Basic and clinical aspects. (2007)
  • Author(s): Moriwaki H
  • Journal Title: Hepatol Res 37
  • NAID: 10019773579
  • Peer Reviewed
• [Journal Article] Synergistic effects of RXR alpha and PPAR gamma ligands to inhibit growth in human colon cancer cells-phosphorylated RXR alpa is a critical target for colon cancer management. (2007)
  • Author(s): Yamazaki K
  • Journal Title: Gut 56 Pages: 1557-1563
  • Peer Reviewed
• [Journal Article] Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells. (2007)
  • Author(s): Kanamori T
  • Journal Title: Cancer Sci 98 Pages: 431-437
  • Peer Reviewed
• [Presentation] シンポジウム肝がん予防の総合戦略と化学予防 (2008)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] シンポジウム 肝がん予防の総合戦略と化学予防 (2008)
  • Author(s): 森脇久隆
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-29
• [Presentation] シンポジウム6「肝癌の分子標的治療」Retinoid核内受容体RXRαを標的分子としたAcyclic retinoidによる肝癌化学予防 (2008)
  • Author(s): 清水雅仁、森脇久隆
  • Organizer: JDDW2008
  • Place of Presentation: 東京
  • Year and Date: 2008-10-01
• [Presentation] シンポジウム6「肝癌の分子標的治療」Retino id核内受容体RXRαを標的分子としたAcyclic retinoidによる肝癌化学予防 (2008)
  • Author(s): 清水雅仁, 森脇久隆
  • Organizer: JDDW2008
  • Place of Presentation: 東京
  • Year and Date: 2008-10-01
• [Presentation] レチノイドとTrastuzumabの併用処理による相乗的な肝癌細胞増殖抑制効果の検討 (2008)
  • Author(s): 建部英春、清水雅仁、森脇久隆
  • Organizer: 第44回日本肝臓学会総会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-05
• [Presentation] パネルディスカッション8「肝癌再発進展阻止を目指して」レチノイド核内受容体RXRαを標的分子とした肝細胞癌化学予防-非環式レチノイドとclonal deletion- (2008)
  • Author(s): 森脇久隆
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2008-05-09
• [Presentation] パネルディスカッション8「肝癌再発進展阻止を目指して」レテノイド核内受容体RXRαを標的分子とした肝細胞癌化学予防-非環式レチノイドとclonal deletion- (2008)
  • Author(s): 清水雅仁, 森脇久隆
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2008-05-09
• [Presentation] Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells (2008)
  • Author(s): Tatebe H, Shimizu M, Shirakami Y, Tsurumi H, Moriwaki H
  • Organizer: 99^<th> AACR(American Association for Cancer Research)Annual Meeting
  • Place of Presentation: サンディエゴ
  • Year and Date: 2008-04-15
• [Presentation] Synergistic growth inhibition by 9-cis-retinoic acid lustrastuzumab in human hepatocellular carcinoma cells. (2008)
  • Author(s): Tatebe H, et al.
  • Organizer: 99^<th> AACR (American Association for Cancer Research) Annual Meeting.
  • Place of Presentation: サッディエゴ・アメリカ
  • Year and Date: 2008-04-15
• [Presentation] ヒト大腸癌におけるRXRαのリン酸化とRXR/PPARγリガンド併用処理による大腸癌細胞増殖抑制効果の検討 (2007)
  • Author(s): 山崎健路、清水雅仁、西脇理英、奥野正隆、小嶋聡一、森脇久隆
  • Organizer: 日本レチノイド研究会第18回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-24
• [Presentation] RXRのリン酸化修飾がRXR/RAR二量体形成能に及ぼす影響についての検討 (2007)
  • Author(s): 吉村光太郎、清水雅仁、西脇理英、奥野正隆、小嶋聡一、武藤吉徳、森脇久隆
  • Organizer: 日本レチノイド研究会第18回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2007-11-24
• [Presentation] Strategy and mechanism for the prevention of hepatocellular carcinoma(HCC)-Phosphorylated RXRα might be a critical target for HCC chemoprevention- (2007)
  • Author(s): Shimizu M, Moriwaki H.
  • Organizer: The 8th Japan-Korea Cancer and Ageing Symposium
  • Place of Presentation: 岐阜
  • Year and Date: 2007-08-11
• [Presentation] Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells (2007)
  • Author(s): Tatebe H, Shimizu M, Shirakami Y, Sakai H, Moriwaki H.
  • Organizer: The 8^<th> Japan-Korean Cancer and Ageing Symposium
  • Place of Presentation: 岐阜
  • Year and Date: 2007-08-11
• [Presentation] Strategy and mechanism for the prevention of hepatocellular carcinoma (MCC)-Phosphorylated RXRa might be a criticaltarget for HCC chemoprevention- (2007)
  • Author(s): Shimizu M
  • Organizer: The 8th Japan-Korea Cancer and Ageing Symposium
  • Place of Presentation: 岐阜
  • Year and Date: 2007-08-11
• [Presentation] Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells. (2007)
  • Author(s): Tatebe H
  • Organizer: The 8th Japan-Korea Cancer and Ageing Symposium
  • Place of Presentation: 岐阜
  • Year and Date: 2007-08-11
• [Presentation] ワークショップ5「肝細胞癌根治療法後の再発抑制」非環式レチノイドとビタミンK2の併用処理による相乗的な肝癌細胞増殖抑制効果の検討 (2007)
  • Author(s): 金森堂、清水雅仁、森脇久隆
  • Organizer: 第93回日本消化器病学会総会
  • Place of Presentation: 青森
  • Year and Date: 2007-04-21
• [Presentation] 非環式レチノイドとビタミンK2の併用処理による相乗的な肝癌細胞増殖抑制効果の検討 (2007)
  • Author(s): 金森 堂
  • Organizer: 第93回日本消化器病学会総会
  • Place of Presentation: 青森
  • Year and Date: 2007-04-21
• [Book] 「第5章病態栄養と栄養療法、7その他の疾患、(木)がん」 : 改訂第2版認定病態栄養専門師のための病態栄養ガイドブック (2008)
  • Author(s): 森脇久隆
  • Publisher: 東京 : メディカルレビュー社
• [Book] 改訂第2版 認定 病態栄養専門師のための病態栄養ガイドブック (2008)
  • Author(s): 森脇久隆
  • Total Pages: 356
  • Publisher: メディカルレビュー社
• [Book] 非環式レチノイドによる肝発癌の予防 : 西口修平編. 肝硬変のマネジメント (2007)
  • Author(s): 清水雅仁, 森脇久隆
  • Publisher: 東京 : 医薬ジャーナル社
• [Book] 肝硬変のマネジメント (2007)
  • Author(s): 清水雅仁, 森脇久隆
  • Total Pages: 321
  • Publisher: 医学書院