Signaling mechanism of antiproliferative effect of HGF on carcinoma cells

• Project/Area Number: 19570124
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: TANAKA Toshiaki Tokyo Institute of Technology, 大学院・生理工学研究科, 助教 (40263446)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 肝細胞増殖因子 / 癌 / HepG2 / 癌抑制因子 / p16 / Id1 / 不可逆的増殖停止 / 細胞周期 / シグナル伝達 / Ets

Research Abstract

HGF による肝癌細胞株HepG2の増殖抑制の鍵となるErkの強活性化には、HGF受容体c-Metにアダプター因子Grb2とGab1が結合することが必要であることを明らかにした。また、HGF刺激により転写制御因子Id1の発現量が減少し、それにより癌抑制因子p16が発現上昇することを見出した。Id1とp16は不可逆的細胞変化である細胞老化に係わることから、HGF刺激が不可逆的増殖停止を誘導する可能性を検討した結果、48時間以上のHGF刺激によりHepG2細胞の増殖停止が不可逆的になることを見出した。この結果は、HGF刺激により癌細胞が癌細胞でなくなることを示す重大な発見となった。

Research Products

• [Journal Article] Id1 is downregulated by hepatocyte growth factor via ERK-dependent and -independent signaling pathways, leading to increased expression of p16INK4a in hepatoma cells. (2009)
  • Author(s): K. Ushio T. Hashimoto, N. Kitamura, T. Tanaka^*
  • Journal Title: Molecular Cancer Research (In press)
  • Peer Reviewed
• [Journal Article] Up-regulation of p21^<CIP1> expressionmediated by ERK-dependent and-independent pathways contributes tohepatocyte growth factor inducedinhibition of HepG2 hepatoma cellproliferation (2008)
  • Author(s): E.Shirako, N.Hirayama, Y.Tsukada,T.Tanaka and N.Kitamura
  • Journal Title: J.Cell.Biochem 104 Pages: 176-188
  • Peer Reviewed
• [Journal Article] Coupling of Grb2 to Gab1 mediateshepatocyte growth factor-induced highintensity ERK signal required forinhibition of HepG2 hepatoma cellproliferation (2008)
  • Author(s): A.Kondo, N.Hirayama, Y.Sugito, M.Shono,T.Tanaka and N.Kitamura
  • Journal Title: J.Biol.Chem 283 Pages: 1428-1436
  • Peer Reviewed
• [Journal Article] Coupling of Grb2 to Gab1 mediates hepatocyte growth factor-induced high intensity ERK signal required for inhibition of HepG2 hepatoma cell proliferation. (2008)
  • Author(s): Asuka KONDO
  • Journal Title: J. Biol. Chem. 283 Pages: 1428-1436
  • Peer Reviewed
• [Journal Article] Up-regulation of p21^CIP1 expression mediated by ERK-dependent and-independent pathways contributes to hepatocyte growth factor induced inhibition of HepG2 hepatoma cell proliferation. (2008)
  • Author(s): Erika SHIRAKO
  • Journal Title: J. Cell. Biochem. (in press)
  • Peer Reviewed
• [Journal Article] Id1 is downregulated byhepatocyte growth factor viaERK-dependent and-independent signalingpathways, leading to increased expressionof p16INK4a in hepatoma cells
  • Author(s): K.Ushio, T.Hashimoto, N.Kitamura and T.Tanaka
  • Journal Title: Mol.CancerRes (in press)
  • Peer Reviewed
• [Presentation] 肝癌細胞株HepG2における肝細胞増殖因子HGFによるp16^<INK4a> 発現制御の分子機構 (2007)
  • Author(s): 潮和敬、喜多村直実、田中利明
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会
  • Place of Presentation: 於 : パシフィコ横浜、ヨコハマグランドインターコンチネンタルホテル
  • Year and Date: 2007-12-11
• [Presentation] 肝癌細胞株HepG2における肝細胞増殖因子HGFによるp16INK4a発現制御の分子機構 (2007)
  • Author(s): 潮 和敬
  • Organizer: 日本分子生物学会年会・日本生化学会大会 合同大会
  • Place of Presentation: パシフィコ横浜、横浜グランドインターコンチネンタルホテル
  • Year and Date: 2007-12-11
• [Presentation] Mechanism ofHGF-induced upregulation of p16INK4a inHepG2 hepatoma cells (2007)
  • Author(s): Kazutaka Ushio, Naomi Kitamura and Toshiaki Tanaka
  • Organizer: The Toin International Symposium on Biomedical Engineering Engineering 2007
  • Place of Presentation: 於 : 桐蔭横浜大学
  • Year and Date: 2007-11-02
• [Presentation] Mechanism of HGF-induced upregulation of p16INK4a in HepG2 hepatoma cells. (2007)
  • Author(s): Kazutaka USHIO
  • Organizer: The Toin International Symposium on Biomedical Engineering 2007.
  • Place of Presentation: 桐蔭横浜大学
  • Year and Date: 2007-11-02